ABSTRACT

The aging population poses a serious challenge concerning an increased prevalence of Alzheimer’s disease (AD) and its impact on global burden, morbidity, and mortality. Oxidative stress, as a molecular hallmark that causes susceptibility in AD, interplays to other AD-related neuropathology cascades and decreases the expression of central and circulation brain-derived neurotrophic factor (BDNF), an essential neurotrophin that serves as nerve development and survival, and synaptic plasticity in AD. By its significant correlation with the molecular and clinical progression of AD, BDNF can potentially be used as an objectively accurate biomarker for AD diagnosis and progressivity follow-up in future clinical practice. This comprehensive review highlights the oxidative stress interplay with BDNF in AD neuropathology and its potential use as an AD biomarker.

Keywords:
Alzheimer Disease; Oxidative Stress; Brain-Derived Neurotrophic Factor; Biomarkers; Antioxidants

RESUMO

O envelhecimento da população representa um sério desafio no que diz respeito ao aumento da prevalência da doença de Alzheimer (DA) e o seu impacto na carga, morbidade e mortalidade globais. O estresse oxidativo, como uma marca molecular que causa suscetibilidade na DA, interage com outras cascatas de neuropatologia relacionadas à DA e diminui a expressão do fator neurotrófico encefálico (brain-derived neurotrophic factor – BDNF), uma neurotrofina essencial que serve como desenvolvimento e sobrevivência nervosa, e plasticidade sináptica na DA. Pela sua correlação significativa com a progressão molecular e clínica da DA, o BDNF pode potencialmente ser usado como um biomarcador objetivamente preciso para o diagnóstico da DA e acompanhamento da progressividade na prática clínica futura. Esta revisão abrangente destacou a interação do estresse oxidativo com o BDNF na neuropatologia da DA e seu uso potencial como biomarcador da DA.

Palavras-chave:
Doença de Alzheimer; Estresse Oxidativo; Fator Neurotrófico Derivado do Encéfalo; Encéfalico; Biomarcadores; Antioxidantes

INTRODUCTION

Alzheimer’s disease (AD), the foremost irreversible neurological disorder, is the fifth leading cause of death and one of the significant global burdens of diseases; it poses a serious challenge in the aging population that requires research focusing more on the early detection and prevention of AD progression¹1 Nichols E, Szoeke CEI, Vollset SE, Abbasi N, Abd-Allah F, Abdela J, et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2018;18:88-106. https://doi.org/10.1016/S1474-4422(18)30403-4
https://doi.org/10.1016/S1474-4422(18)30... –³3 Brayne C, Miller B. Dementia and aging populations – a global priority for contextualized research and health policy. PLoS Med. 2017;14(3):e1002275. https://doi.org/10.1371/journal.pmed.1002275
https://doi.org/10.1371/journal.pmed.100... . Accurate biomarkers for early AD detection and progression rate monitoring are essential in prevention strategies and assessing therapeutic efficacy. The importance of accelerating research in this regard is because we are pacing with time, along with the increased AD prevalence exponentially with age, and the doubling dementia incidence per year, that projected around ten million additional cases per year, reaching 152 million cases by 2050⁴4 Corrada MM, Brookmeyer R, Paganini-Hill A, Berlau D, Kawas CH. Dementia incidence continues to increase with age in the oldest old the 90+ study. Ann Neurol. 2010;67:114-21. https://doi.org/10.1002/ana.21915
https://doi.org/10.1002/ana.21915... ,⁵5 World Health Organization. Dementia [Internet]. 2023 [cited on Oct 9, 2022]. Available from: https://www.who.int/news-room/fact-sheets/detail/dementia
https://www.who.int/news-room/fact-sheet... . This comprehensive review is limited to the study of the brain-derived neurotrophic factor (BDNF) as a potential biomarker for AD diagnosis and progression, the complex effects of oxidative stress (OS) in the neuropathology of AD, and the interplay between BDNF, OS, and AD continuum. This study was conducted using extensive research on PubMed, DOAJ, EBSCO, and Google Scholar databases with publications within the last thirty years, prioritizing clinical trials, in vivo and in vitro studies, randomized controlled trials, and comprehensive review articles. The keywords used for the selection of the pieces were focused on ‘Alzheimer’s disease’, ‘dementia’, ‘cognitive impairment’, ‘aging’, ‘oxidative stress’, ‘reactive oxygen species’, ‘biomarker’, and ‘brain-derived neurotrophic factor’ or ‘BDNF’ and those synonyms. Studies that were irrelevant to this review’s limitation were excluded.

The complexity of AD neuropathology from the genetic, molecular, and anatomic to clinical levels that are influenced by multiple causes, makes important and necessary a paradigm shift toward a multimodal and multispecialty approach in treating AD⁶6 Turana Y, Ranakusuma TAS, Purba JS, Amir N, Ahmad SA, Machfoed MH, et al. Enhancing diagnostic accuracy of aMCI in the elderly: combination of olfactory test, pupillary response test, BDNF plasma level, and APOE genotype. Int J Alzheimers Dis. 2014;2014:912586. https://doi.org/10.1155/2014/912586
https://doi.org/10.1155/2014/912586... –¹⁰10 Bekris LM, Yu CE, Bird TD, Tsuang DW. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol. 2010;23(4):213-27. https://doi.org/10.1177/0891988710383571
https://doi.org/10.1177/0891988710383571... . OS is one of the findings postulated to be involved in the aging process and neurodegenerative diseases, including AD¹¹11 Dasgupta A, Klein K. Role of oxidative stress in neurodegenerative diseases and other diseases related to aging. In: Dasgupta A, Klein K, eds. Antioxidants in food, vitamins and supplements. San Diego: Elsevier; 2014. p. 167-84.. Aggregation of β-amyloid (Aβ) plaque and neurofibrillary tangles (NFTs) as the main clinical hallmarks of AD was closely associated with increased reactive oxygen species (ROS) production that caused OS as a result of mitochondrial damage and neuronal dysfunction¹²12 Uddin MS, Kabir MT. Oxidative stress in Alzheimer’s disease: molecular hallmarks of underlying vulnerability. In: Ashraf GM, Alexiou A, eds. Biological, diagnostic and therapeutic advances in Alzheimer’s disease: non-pharmacological therapies for Alzheimer’s disease. Singapore: Springer; 2019. p. 91-115. https://doi.org/10.1007/978-981-13-9636-6_5
https://doi.org/10.1007/978-981-13-9636-... ,¹³13 Fischer R, Maier O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev. 2015;2015:e610813. https://doi.org/10.1155/2015/610813
https://doi.org/10.1155/2015/610813... . OS is also cited as a molecular hallmark that causes susceptibility in AD and increases the aggregation and production of Aβ and phosphorylation of tau protein leading to a vicious circular process in AD progression¹²12 Uddin MS, Kabir MT. Oxidative stress in Alzheimer’s disease: molecular hallmarks of underlying vulnerability. In: Ashraf GM, Alexiou A, eds. Biological, diagnostic and therapeutic advances in Alzheimer’s disease: non-pharmacological therapies for Alzheimer’s disease. Singapore: Springer; 2019. p. 91-115. https://doi.org/10.1007/978-981-13-9636-6_5
https://doi.org/10.1007/978-981-13-9636-... ,¹⁴14 Zuo L, Hemmelgarn BT, Chuang CC, Best TM. The role of oxidative stress-induced epigenetic alterations in amyloid-β production in Alzheimer’s disease. Oxid Med Cell Longev. 2015;2015:604658. https://doi.org/10.1155/2015/604658
https://doi.org/10.1155/2015/604658... .

OS decreased the expression and levels of BDNF, the most widely distributed neurotrophin in the brain, that plays an essential role in AD neuropathology, in nerve development and survival, and synaptic plasticity¹⁵15 Wang M, Xie Y, Qin D. Proteolytic cleavage of proBDNF to mBDNF in neuropsychiatric and neurodegenerative diseases. Brain Res Bull. 2021;166:172-84. https://doi.org/10.1016/j.brainresbull.2020.11.005
https://doi.org/10.1016/j.brainresbull.2... –¹⁸18 Wu A, Ying Z, Gomez-Pinilla F. The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition. Eur J Neurosci. 2004;1997):1699-707. https://doi.org/10.1111/j.1460-9568.2004.03246.x
https://doi.org/10.1111/j.1460-9568.2004... . AD patients have significantly lower circulating BDNF levels, especially in the temporal, frontal, and parietal lobes, along with severely reduced BDNF mRNA in the hippocampus and parietal cortex, which leads to cholinergic cell atrophy and dysfunction¹⁹19 Dineley KT, Xia X, Bui D, Sweatt JD, Zheng H. Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins. J Biol Chem. 2002;277(25):22768-80. https://doi.org/10.1074/jbc.M200164200
https://doi.org/10.1074/jbc.M200164200... –²³23 Holsinger RM, Schnarr J, Henry P, Castelo VT, Fahnestock M. Quantitation of BDNF mRNA in human parietal cortex by competitive reverse transcription-polymerase chain reaction: decreased levels in Alzheimer’s disease. Brain Res Mol Brain Res. 2000;76(2):347-54. https://doi.org/10.1016/s0169-328x(00)00023-1
https://doi.org/10.1016/s0169-328x(00)00... . BDNF can potentially be used as an objectively accurate AD biomarker as it correlates and is directly linked with the cerebral phenomenon of AD, and decreased BDNF levels are also correlated with the degree of cognitive decline and neurological impairment reflecting the AD progressivity²⁴24 Balietti M. Blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease. In: Martin CR, Preedy VR, eds. Diagnosis and management in dementia. Academic Press; 2020. p. 281-96.,²⁵25 Fahnestock M. Brain-derived neurotrophic factor: the link between amyloid-β and memory loss. Future Neurology. 2011;6:627-39. https://doi.org/10.2217/fnl.11.44
https://doi.org/10.2217/fnl.11.44... . Further discussion of BDNF interplay with OS in AD neuropathology and BDNF potential as a diagnostic biomarker and progressivity follow-up will be presented in this review.

Overview of oxidative stress and its detrimental effects on health

Research on ROS has developed quite rapidly and comprehensively in the last two decades. ROS, which are by-products of aerobic metabolism, play a role in tissue damage in OS conditions and also have an important role in cell signaling pathways, both in various diseases. OS is an imbalance condition of redox state when the amount of pro-oxidants exceeds antioxidants²⁶26 Sies H. Oxidative stress: eustress and distress in redox homeostasis. In: Fink G, ed. Stress: physiology, biochemistry, and pathology. Academic Press; 2019. p. 153-63. https://doi.org/10.1016/B978-0-12-813146-6.00013-8
https://doi.org/10.1016/B978-0-12-813146... ,²⁷27 Shankar K, Mehendale HM. Oxidative stress. In: Wexler P, editor. Encyclopedia of toxicology. 3rd ed. Oxford: Academic Press; 2014. p. 735-7.. Under certain conditions, the balance of the system in the body, which is maintained by deoxyribonucleic acid (DNA), protein, carbohydrates, and lipids, is damaged by ROS, which causes the disruption of metabolic status, cell growth, and cell development²⁸28 Keshari A, Verma AK, Kumar T, Srivastava R. Oxidative stress: a review. International Journal of Science & Technoledge. 2015;3(7):155-62.. ROS cause OS by breaking the cellular DNA chain and damaging nitrogenous bases, which results in exposure to hydroxyl radical (^•OH), one-electron oxidants, singlet oxygen (¹1 Nichols E, Szoeke CEI, Vollset SE, Abbasi N, Abd-Allah F, Abdela J, et al. Global, regional, and national burden of Alzheimer’s disease and other dementias, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2018;18:88-106. https://doi.org/10.1016/S1474-4422(18)30403-4
https://doi.org/10.1016/S1474-4422(18)30... O₂^•), and hypochlorous acid (HOCl)²⁸28 Keshari A, Verma AK, Kumar T, Srivastava R. Oxidative stress: a review. International Journal of Science & Technoledge. 2015;3(7):155-62.,²⁹29 Cadet J, Wagner JR. DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harb Perspect Biol. 2013;5(2):a012559. https://doi.org/10.1101/cshperspect.a012559
https://doi.org/10.1101/cshperspect.a012... . One-electron oxidant was found to potentially decrease the DNA base by order of guanine less reduced than adenine, and both less decreased than cytosine and thymine²⁹29 Cadet J, Wagner JR. DNA base damage by reactive oxygen species, oxidizing agents, and UV radiation. Cold Spring Harb Perspect Biol. 2013;5(2):a012559. https://doi.org/10.1101/cshperspect.a012559
https://doi.org/10.1101/cshperspect.a012... . OS generated by cell metabolism, an endogenous process or exogenous process by exposome, can be triggered by various causes of tissue damage physically, chemically, or microbially; including infectious conditions, impaired blood vessel perfusion, toxins, radiation, extreme temperature, excessive exercise, and traumatic injury²⁶26 Sies H. Oxidative stress: eustress and distress in redox homeostasis. In: Fink G, ed. Stress: physiology, biochemistry, and pathology. Academic Press; 2019. p. 153-63. https://doi.org/10.1016/B978-0-12-813146-6.00013-8
https://doi.org/10.1016/B978-0-12-813146... ,³⁰30 Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, et al. Oxidative stress: harms and benefits for human health. Oxid Med Cell Longev. 2017;2017:8416763. https://doi.org/10.1155/2017/8416763
https://doi.org/10.1155/2017/8416763... ,³¹31 Gagné F. Oxidative stress. In: Gagné F, ed. Biochemical ecotoxicology. Oxford: Academic Press; 2014. p. 103-15.. Mitochodria is the major source of endogenous ROS, while the exogenous ROS sources are smoking, air pollutants, and solar ultraviolet radiations (UVR), besides pesticides, environmental chemicals, pollutants, redox-active metals, and ionizing radiations from radioactive decay and x-ray photons³²32 Poljsak B. Strategies for reducing or preventing the generation of oxidative stress. Oxid Med Cell Longev. 2011;2011:194586. https://doi.org/10.1155/2011/194586
https://doi.org/10.1155/2011/194586... –³⁴34 Jomova K, Valko M. Advances in metal-induced oxidative stress and human disease. Toxicology. 2011;283(2-3):65-87. https://doi.org/10.1016/j.tox.2011.03.001
https://doi.org/10.1016/j.tox.2011.03.00... .

ROS, which are sometimes referred to as reactive oxygen metabolites (ROMs) or reactive oxygen intermediates (ROIs), are all reactive species that contain oxygen atoms with unstable and highly reactive properties³⁵35 Li R, Jia Z, Trush MA. Defining ROS in biology and medicine. React Oxyg Species (Apex). 2016;1(1):9-21. https://doi.org/10.20455/ros.2016.803
https://doi.org/10.20455/ros.2016.803... . ROS are divided into two types, namely oxygen free radicals and non-radicals. Free radicals are every atom that is capable of independent existence and contains more than equal to one unpaired electron in its outer valence area, for example, superoxide, hydroxyl, peroxyl, alkoxyl, and hydroperoxyl²⁸28 Keshari A, Verma AK, Kumar T, Srivastava R. Oxidative stress: a review. International Journal of Science & Technoledge. 2015;3(7):155-62.,³⁵35 Li R, Jia Z, Trush MA. Defining ROS in biology and medicine. React Oxyg Species (Apex). 2016;1(1):9-21. https://doi.org/10.20455/ros.2016.803
https://doi.org/10.20455/ros.2016.803... . In contrast, non-radicals are atoms that do not have unpaired electrons, for example, hydrogen peroxide, hypochlorous acid, ozone, singlet oxygen, and peroxynitrite. ROS can be produced during metabolic processes and the immune system in the human body. The ROS themselves are like a double-edged sword, that is, in addition to the damage they cause at functional concentrations, they have beneficial properties for the body, such as being involved in phagocytosis, apoptosis, necrosis, and protection against pathogens. Actually, upregulation of ROS is the body’s adaptation response to cellular stress due to various physiological disorders; this condition is termed oxidative eustress where the OS is at a low level and the goal is to increase cell resistance as a pre-conditioning for acute stress²⁶26 Sies H. Oxidative stress: eustress and distress in redox homeostasis. In: Fink G, ed. Stress: physiology, biochemistry, and pathology. Academic Press; 2019. p. 153-63. https://doi.org/10.1016/B978-0-12-813146-6.00013-8
https://doi.org/10.1016/B978-0-12-813146... ,³⁶36 Bonini MG, Consolaro MEL, Hart PC, Mao M, Abreu ALP, Master AM. Redox control of enzymatic functions: the electronics of life’s circuitry. IUBMB Life. 2014;66(3):167-81. https://doi.org/10.1002/iub.1258
https://doi.org/10.1002/iub.1258... . Whereas the high-level OS, which refers to a pathological condition, is also termed oxidative distress that happens to disrupt redox signaling and molecular oxidative damage²⁶26 Sies H. Oxidative stress: eustress and distress in redox homeostasis. In: Fink G, ed. Stress: physiology, biochemistry, and pathology. Academic Press; 2019. p. 153-63. https://doi.org/10.1016/B978-0-12-813146-6.00013-8
https://doi.org/10.1016/B978-0-12-813146... . Various studies have found a link of OS to various diseases depending on tissue damage in the related organs ranging from neurodegenerative and metabolic disorders to multi-organ conditions including cancer, aging, and age-related diseases³⁰30 Pizzino G, Irrera N, Cucinotta M, Pallio G, Mannino F, Arcoraci V, et al. Oxidative stress: harms and benefits for human health. Oxid Med Cell Longev. 2017;2017:8416763. https://doi.org/10.1155/2017/8416763
https://doi.org/10.1155/2017/8416763... ,³⁷37 Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della-Morte D, et al. Oxidative stress, aging, and diseases. Clin Interv Aging. 2018;13:757-72. https://doi.org/10.2147/CIA.S158513
https://doi.org/10.2147/CIA.S158513... . Mild cognitive impairment (MCI) with AD and its severity progression is also linked to OS.

The production of ROS in cells can occur in the mitochondria, peroxisomes, or through misfolded proteins in the nucleus that cause stress on the endoplasmic reticulum²⁸28 Keshari A, Verma AK, Kumar T, Srivastava R. Oxidative stress: a review. International Journal of Science & Technoledge. 2015;3(7):155-62.,³⁸38 Cao SS, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxid Redox Signal. 2014;21(3):396-413. https://doi.org/10.1089/ars.2014.5851
https://doi.org/10.1089/ars.2014.5851... . Endogenous sub-cellular ROS products involve several enzymes for the generation of ROS, including monoamine oxidase, lipoxygenase, cyclooxygenase, NADPH oxidase, cytochrome p450 monooxygenase, xanthine oxidoreductase, and nitric oxide synthase²⁸28 Keshari A, Verma AK, Kumar T, Srivastava R. Oxidative stress: a review. International Journal of Science & Technoledge. 2015;3(7):155-62.. Exogenous sources usually form ROS by the Fenton and Haber-Weiss reactions, and these two reactions play a significant role in OS in many neurodegenerative diseases³⁹39 Zhao Z. Iron and oxidizing species in oxidative stress and Alzheimer’s disease. Aging Med (Milton). 2019;2(2):82-7. https://doi.org/10.1002/agm2.12074
https://doi.org/10.1002/agm2.12074... –⁴¹41 Carocci A, Catalano A, Sinicropi MS, Genchi G. Oxidative stress and neurodegeneration: the involvement of iron. Biometals. 2018;31:715-35. https://doi.org/10.1007/s10534-018-0126-2
https://doi.org/10.1007/s10534-018-0126-... . In the Fenton reaction, one of the electrons from molecular oxygen is removed to form superoxide anion; then with superoxide dismutase (SOD) it forms hydrogen peroxide (H₂O₂), which reacts with metal transitions (iron/Fe, copper/Cu, zinc/Zn, or aluminum/Al) to form highly ROS, and finally hydroxyl radicals (^•OH) as output²⁸28 Keshari A, Verma AK, Kumar T, Srivastava R. Oxidative stress: a review. International Journal of Science & Technoledge. 2015;3(7):155-62.,³⁹39 Zhao Z. Iron and oxidizing species in oxidative stress and Alzheimer’s disease. Aging Med (Milton). 2019;2(2):82-7. https://doi.org/10.1002/agm2.12074
https://doi.org/10.1002/agm2.12074... ,⁴⁰40 Das TK, Wati MR, Fatima-Shad K. Oxidative stress gated by fenton and haber weiss reactions and its association with Alzheimer’s disease. Arch Neurosci. 2015;2(2):e60038. https://doi.org/10.5812/archneurosci.20078
https://doi.org/10.5812/archneurosci.200... . H₂O₂ which is more stable and permeable to plasma membrane than superoxide, then reacts with superoxide and also forms the hydroxyl radicals (^•OH) and hydroxyl anion (-OH) — this is the Haber-Weiss reaction²⁸28 Keshari A, Verma AK, Kumar T, Srivastava R. Oxidative stress: a review. International Journal of Science & Technoledge. 2015;3(7):155-62.,⁴⁰40 Das TK, Wati MR, Fatima-Shad K. Oxidative stress gated by fenton and haber weiss reactions and its association with Alzheimer’s disease. Arch Neurosci. 2015;2(2):e60038. https://doi.org/10.5812/archneurosci.20078
https://doi.org/10.5812/archneurosci.200... . H₂O₂ through the enzyme myeloperoxidase (MPO) is also able to react with halogen atoms (chlorine/Cl⁻, bromine/Br⁻, and iodine/I⁻) to form hypochlorous acid (HOCl), which is the most reactive and bactericidal ROS, has an important feature as a protective factor against pathogenic invasion, and is closely related to various inflammatory diseases²⁸28 Keshari A, Verma AK, Kumar T, Srivastava R. Oxidative stress: a review. International Journal of Science & Technoledge. 2015;3(7):155-62.,⁴²42 Zheng MH, Hu X, Wang XW, Liu XL, Jin JY. Fluorescence-enhanced sensing of hypochlorous acid based on 2-pyridylthiazole unit. J Fluoresc. 2016;26(2):593-8. https://doi.org/10.1007/s10895-015-1745-4
https://doi.org/10.1007/s10895-015-1745-... . MPO, in a process that irreversibly inactivates through the oxidative burst of neutrophils that occurs in the phagosome, will use H₂O₂ for the production of antimicrobial oxidants; this natural chemical signaling molecule in inflammation would jump-start the neutrophils as first responder in immune system against toxins, parasites, bacteria, viruses, and yeast²⁸28 Keshari A, Verma AK, Kumar T, Srivastava R. Oxidative stress: a review. International Journal of Science & Technoledge. 2015;3(7):155-62.,⁴³43 Paumann-Page M, Furtmüller PG, Hofbauer S, Paton LN, Obinger C, Kettle AJ. Inactivation of human myeloperoxidase by hydrogen peroxide. Arch Biochem Biophys. 2013;539(1):51-62. https://doi.org/10.1016/j.abb.2013.09.004
https://doi.org/10.1016/j.abb.2013.09.00... ,⁴⁴44 Wittmann C, Chockley P, Singh SK, Pase L, Lieschke GJ, Grabher C. Hydrogen peroxide in inflammation: messenger, guide, and assassin. Adv Hematol. 2012;2012:541471. https://doi.org/10.1155/2012/541471
https://doi.org/10.1155/2012/541471... .

The role of oxidative stress in neuropathology of Alzheimer’s disease

Oxidative stress affects aging and Alzheimer’s disease

Aging is an inescapable consequence of entropy that governs the chemical reactions required for life. It is a sequel of time-dependent deterioration of macromolecules with an alteration of our body’s biological system of repair, recycling, and renewal mechanisms⁴⁵45 Prahlad V, Chikka MR. Aging and the brain. In: Rizzo M, Anderson S, Fritzsch B, eds. The Wiley handbook on the aging mind and brain. Chichester: John Wiley & Sons, Ltd; 2018. p. 37-60. https://doi.org/10.1002/9781118772034.ch3
https://doi.org/10.1002/9781118772034.ch... . Several things contribute to evolutionary theories of aging, including cellular mechanisms that drive aging, genomic instability, telomere attrition, mitochondrial damage, protein damage, cellular senescence, altered intercellular signaling, dysregulation of the immune system, altered metabolism, and nutrient signaling⁴⁵45 Prahlad V, Chikka MR. Aging and the brain. In: Rizzo M, Anderson S, Fritzsch B, eds. The Wiley handbook on the aging mind and brain. Chichester: John Wiley & Sons, Ltd; 2018. p. 37-60. https://doi.org/10.1002/9781118772034.ch3
https://doi.org/10.1002/9781118772034.ch... ,⁴⁶46 Johnson AA, Shokhirev MN, Shoshitaishvili B. Revamping the evolutionary theories of aging. Ageing Res Rev. 2019;55:100947. https://doi.org/10.1016/j.arr.2019.100947
https://doi.org/10.1016/j.arr.2019.10094... . During life, somatic cells are continually exposed to exogenous pro-oxidants that trigger ROS formation and are capable of causing genomic alterations due to DNA damage; however, it is difficult to determine whether the accumulation of damaged DNA in cells is a result or a consequence of aging itself⁴⁵45 Prahlad V, Chikka MR. Aging and the brain. In: Rizzo M, Anderson S, Fritzsch B, eds. The Wiley handbook on the aging mind and brain. Chichester: John Wiley & Sons, Ltd; 2018. p. 37-60. https://doi.org/10.1002/9781118772034.ch3
https://doi.org/10.1002/9781118772034.ch... ,⁴⁷47 Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, Yanai H, et al. The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res Rev. 2013;12(2):661-84. https://doi.org/10.1016/j.arr.2012.02.001
https://doi.org/10.1016/j.arr.2012.02.00... .

Lack of DNA repair mechanisms was found in age-related neurodegenerative disease, and accumulation of DNA damage tends to occur in neurons of people with neurological disorders. Since the study of DNA damage in the early 1990s, it was found that DNA strand breakage in the cerebral cortex of the AD group is twofold higher than in healthy elderly⁴⁸48 Mullaart E, Boerrigter ME, Ravid R, Swaab DF, Vijg J. Increased levels of DNA breaks in cerebral cortex of Alzheimer’s disease patients. Neurobiol Aging. 1990;11(3):169-73. https://doi.org/10.1016/0197-4580(90)90542-8
https://doi.org/10.1016/0197-4580(90)905... . The mutation in mitochondrial DNA (mtDNA) is also crucial because it affects the work of electron transport chain (ETC) for oxidative phosphorylation. Consequently, it disrupts the respiratory function of cells, causes an abnormal increase in ROS production, and dysregulation of ROS-dependent cellular signaling pathway. This induces abnormal OS, and over lifetime causes metabolic alterations, chronic inflammatory responses, and age-dependent tissue degeneration and dysfunction due to accumulation of cellular damage, respiratory deficiency, and decreasing adenosine triphosphate (ATP), required for cellular functional work⁴⁵45 Prahlad V, Chikka MR. Aging and the brain. In: Rizzo M, Anderson S, Fritzsch B, eds. The Wiley handbook on the aging mind and brain. Chichester: John Wiley & Sons, Ltd; 2018. p. 37-60. https://doi.org/10.1002/9781118772034.ch3
https://doi.org/10.1002/9781118772034.ch... ,⁴⁹49 Gurung P, Lukens JR, Kanneganti TD. Mitochondria: diversity in the regulation of the NLRP3 inflammasome. Trends Mol Med. 2015;21(3):193-201. https://doi.org/10.1016/j.molmed.2014.11.008
https://doi.org/10.1016/j.molmed.2014.11... ,⁵⁰50 Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet. 1989;1(8639):642-5. https://doi.org/10.1016/s0140-6736(89)92145-4
https://doi.org/10.1016/s0140-6736(89)92... . It should be noted that the frequency of mtDNA mutations is higher than nuclear genome mutations because the mtDNA lacks protective histones and repair enzymes, and mitochondria work in an oxidative microenvironment, so that damage to mitochondrial functionality is more susceptible to triggering OS⁵⁰50 Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet. 1989;1(8639):642-5. https://doi.org/10.1016/s0140-6736(89)92145-4
https://doi.org/10.1016/s0140-6736(89)92... . In the post-mortem brain sample of AD patients, it was found that there was mitochondrial genomic dysfunction as indicated by the high percentage of cytochrome c oxidase-deficient neurons and the high number of mutations and degraded mtDNA in neurons with ETC disorders⁴⁵45 Prahlad V, Chikka MR. Aging and the brain. In: Rizzo M, Anderson S, Fritzsch B, eds. The Wiley handbook on the aging mind and brain. Chichester: John Wiley & Sons, Ltd; 2018. p. 37-60. https://doi.org/10.1002/9781118772034.ch3
https://doi.org/10.1002/9781118772034.ch... ,⁵¹51 Edgar D, Trifunovic A. The mtDNA mutator mouse: dissecting mitochondrial involvement in aging. Aging (Albany NY). 2009;1(12):1028-32. https://doi.org/10.18632/aging.100109
https://doi.org/10.18632/aging.100109... –⁵³53 Reddy PH. Amyloid beta, mitochondrial structural, and functional dynamics in Alzheimer’s disease. Exp Neurol. 2009;218(2):286-92. https://doi.org/10.1016/j.expneurol.2009.03.042
https://doi.org/10.1016/j.expneurol.2009... . In addition, a base excision repair (BER) pathway that functions for DNA repair was found defective in the mitochondria of AD patients⁴⁵45 Prahlad V, Chikka MR. Aging and the brain. In: Rizzo M, Anderson S, Fritzsch B, eds. The Wiley handbook on the aging mind and brain. Chichester: John Wiley & Sons, Ltd; 2018. p. 37-60. https://doi.org/10.1002/9781118772034.ch3
https://doi.org/10.1002/9781118772034.ch... ,⁵¹51 Edgar D, Trifunovic A. The mtDNA mutator mouse: dissecting mitochondrial involvement in aging. Aging (Albany NY). 2009;1(12):1028-32. https://doi.org/10.18632/aging.100109
https://doi.org/10.18632/aging.100109... –⁵³53 Reddy PH. Amyloid beta, mitochondrial structural, and functional dynamics in Alzheimer’s disease. Exp Neurol. 2009;218(2):286-92. https://doi.org/10.1016/j.expneurol.2009.03.042
https://doi.org/10.1016/j.expneurol.2009... .

The occurrence of OS is closely related to the optimal work of mitochondrial cells¹³13 Fischer R, Maier O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev. 2015;2015:e610813. https://doi.org/10.1155/2015/610813
https://doi.org/10.1155/2015/610813... . In healthy cells, a source of free radical superoxide can be produced in the ETC during mitochondrial activity or generation by NADPH oxidases, which are enzyme complexes in the cell membrane, that is involved in cell signaling and tissue homeostasis¹³13 Fischer R, Maier O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev. 2015;2015:e610813. https://doi.org/10.1155/2015/610813
https://doi.org/10.1155/2015/610813... ,⁵⁴54 Cooney SJ, Bermudez-Sabogal SL, Byrnes KR. Cellular and temporal expression of NADPH oxidase (NOX) isotypes after brain injury. J Neuroinflammation. 2013;10:155. https://doi.org/10.1186/1742-2094-10-155
https://doi.org/10.1186/1742-2094-10-155... ,⁵⁵55 Gao HM, Zhou H, Hong JS. NADPH oxidases: novel therapeutic targets for neurodegenerative diseases. Trends Pharmacol Sci. 2012;33(6):295-303. https://doi.org/10.1016/j.tips.2012.03.008
https://doi.org/10.1016/j.tips.2012.03.0... . Superoxide is converted directly to H₂O₂ by SOD in the mitochondrial matrix and cytosol to prevent the inactivation of proteins containing iron-sulfur clusters in the mitochondrion⁵⁶56 Urrutia PJ, Mena NP, Núñez MT. The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders. Front Pharmacol. 2014;5:38. https://doi.org/10.3389/fphar.2014.00038
https://doi.org/10.3389/fphar.2014.00038... . Then the H₂O₂ is rapidly converted to water in the glutathione (GSH) redox cycle, including GSH reductase and peroxiredoxins, which are important defense mechanisms in the protection of cell membranes against OS; the purpose is to prevent the continuation of the Fenton reaction in making the most harmful ROS, namely hydroxyl radical, besides, it also reduces the oxidation of lipid molecules¹³13 Fischer R, Maier O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev. 2015;2015:e610813. https://doi.org/10.1155/2015/610813
https://doi.org/10.1155/2015/610813... ,⁵⁷57 Marí M, Morales A, Colell A, García-Ruiz C, Kaplowitz N, Fernández-Checa JC. Mitochondrial glutathione: features, regulation and role in disease. Biochim Biophys Acta. 2013;1830(5):3317-28. https://doi.org/10.1016/j.bbagen.2012.10.018
https://doi.org/10.1016/j.bbagen.2012.10... .

Increased mitochondrial damage and dysfunction in neurons in AD caused by Aβ, that directly bind to mitochondria and interfere with imports of mitochondrial proteins, cause the impairment of ETC function associated with up-regulation of the nitric oxide synthase (NOS) and NADPH oxidase (NOX) genes, and, consequently increases ROS production oxidative stress indexes (OSI) in AD⁵⁸58 de la Monte SM, Wands JR. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer’s disease. J Alzheimer’s Dis. 2006;9(2):167-81. https://doi.org/10.3233/jad-2006-9209
https://doi.org/10.3233/jad-2006-9209... ,⁵⁹59 Devi L, Prabhu BM, Galati DF, Avadhani NG, Anandatheerthavarada HK. Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer’s disease brain is associated with mitochondrial dysfunction. J Neurosci. 2006;26(35):9057-68. https://doi.org/10.1523/JNEUROSCI.1469-06.2006
https://doi.org/10.1523/JNEUROSCI.1469-0... . However, like a vicious cycle, OS also increases the generation of Aβ peptides and the formation of NFTs by activating the c-jun N-terminal kinase (JNK) and p38 MAP kinase (MAPK), which then increases β-secretase expression by activating glycogen synthase kinase-3 (GSK3), which causes tau hyperphosphorylation (Figure 1)⁶⁰60 Tamagno E, Parola M, Bardini P, Piccini A, Borghi R, Guglielmotto M, et al. Beta-site APP cleaving enzyme up-regulation induced by 4-hydroxynonenal is mediated by stress-activated protein kinases pathways. J Neurochem. 2005;92(3):628-36. https://doi.org/10.1111/j.1471-4159.2004.02895.x
https://doi.org/10.1111/j.1471-4159.2004... ,⁶¹61 Lovell MA, Xiong S, Xie C, Davies P, Markesbery WR. Induction of hyperphosphorylated tau in primary rat cortical neuron cultures mediated by oxidative stress and glycogen synthase kinase-3. J Alzheimer’s Dis. 2004;6(6):659-71; discussion 673-81. https://doi.org/10.3233/jad-2004-6610
https://doi.org/10.3233/jad-2004-6610... .

Oxidative stress in Alzheimer’s disease neuropathology

The AD neuropathology is very complex, involving various aspects such as neurodegeneration, chronic inflammation, neurogenesis, disruption of the blood-brain barrier (BBB), vascular homeostasis, impaired cellular signaling, and decreased neurotrophic factors, as well as disorders at the molecular level caused by OS and at the genetic level caused by several genetic variations and mutations, yet aggravated by other chronic and metabolic diseases (Figure 1)⁶6 Turana Y, Ranakusuma TAS, Purba JS, Amir N, Ahmad SA, Machfoed MH, et al. Enhancing diagnostic accuracy of aMCI in the elderly: combination of olfactory test, pupillary response test, BDNF plasma level, and APOE genotype. Int J Alzheimers Dis. 2014;2014:912586. https://doi.org/10.1155/2014/912586
https://doi.org/10.1155/2014/912586... –¹⁰10 Bekris LM, Yu CE, Bird TD, Tsuang DW. Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol. 2010;23(4):213-27. https://doi.org/10.1177/0891988710383571
https://doi.org/10.1177/0891988710383571... . The hallmarks of AD neuropathology are the formation and accumulation of highly insoluble densely packed filaments of Aβ plaque extracellularly and NFTs intracellularly in the brain⁶²62 Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014;71(4):505-8. https://doi.org/10.1001/jamaneurol.2013.5847
https://doi.org/10.1001/jamaneurol.2013.... ,⁶³63 Kumar V, Abbas A, Aster J. The central nervous system. In: Kumar V, Abbas A, Aster J, eds. Robbins & Cotran pathologic basis of disease. 10th ed. Philadelphia: Elsevier; 2021. p. 1275-8.. Accumulation of Aβ plaques and NFTs correlated with the progression of memory and cognitive impairment by its cause of neuronal synapse damage, although AD severity is also contributed by multifactorial co-pathology⁶²62 Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014;71(4):505-8. https://doi.org/10.1001/jamaneurol.2013.5847
https://doi.org/10.1001/jamaneurol.2013.... ,⁶⁴64 Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol. 2012;71(5):362-81. https://doi.org/10.1097/NEN.0b013e31825018f7
https://doi.org/10.1097/NEN.0b013e318250... .

Aβ plaque is a formation of amyloid fibrils formed from the aggregation of oligomers due to the accumulation of a number of Aβ peptide monomers. The formation of these monomers is due to the amyloidogenic peptides cleavage of extracellular transmembrane proteins of amyloid precursor protein (APP) by β-secretase and γ-secretase, which in physiological processing by α-secretase and γ-secretase in the non-amyloidogenic peptides cleavage pathway is thought to have function for modulating a cell and neurite growth and survival⁶³63 Kumar V, Abbas A, Aster J. The central nervous system. In: Kumar V, Abbas A, Aster J, eds. Robbins & Cotran pathologic basis of disease. 10th ed. Philadelphia: Elsevier; 2021. p. 1275-8.,⁶⁵65 O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci. 2011;34:185-204. https://doi.org/10.1146/annurev-neuro-061010-113613
https://doi.org/10.1146/annurev-neuro-06... –⁶⁸68 Colvin MT, Silvers R, Ni QZ, Can TV, Sergeyev I, Rosay M, et al. Atomic resolution structure of monomorphic Aβ42 amyloid fibrils. J Am Chem Soc. 2016;138(30):9663-74. https://doi.org/10.1021/jacs.6b05129
https://doi.org/10.1021/jacs.6b05129... . On the other hand, the nerve axon that contained an abundance of microtubule-associated protein (MAP) tau has a role in promoting the stabilization of microtubules (MTs) of its six tau isoforms that compose the MT-binding domain⁶⁹69 Ballatore C, Lee VMY, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8(9):663-72. https://doi.org/10.1038/nrn2194
https://doi.org/10.1038/nrn2194... ,⁷⁰70 Buée L, Bussière T, Buée-Scherrer V, Delacourte A, Hof PR. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Rev. 2000;33(1):95-130. https://doi.org/10.1016/s0165-0173(00)00019-9
https://doi.org/10.1016/s0165-0173(00)00... . The condition of tau hyperphosphorylation caused by indirect events (Aβ mediated neurotoxicity, OS, and chronic inflammation) as in AD, and the direct events (aberrant activation of tau kinases, downregulation of phosphatases, mutations, and covalent modifications of tau), will cause a loss of binding between MAP tau and MTs and trigger the formation of NFTs aggregation composed of misfolded tau protein deposits in neurons or glia cells, also called tauopathies, that would cause neurotoxicity and compromised axonal transport⁶⁹69 Ballatore C, Lee VMY, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8(9):663-72. https://doi.org/10.1038/nrn2194
https://doi.org/10.1038/nrn2194... ,⁷¹71 Roch JM, Masliah E, Roch-Levecq AC, Sundsmo MP, Otero DA, Veinbergs I, et al. Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor. Proc Natl Acad Sci USA. 1994;91(16):7450-4. https://doi.org/10.1073/pnas.91.16.7450
https://doi.org/10.1073/pnas.91.16.7450... –⁷³73 Tai HC, Serrano-Pozo A, Hashimoto T, Frosch MP, Spires-Jones TL, Hyman BT. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am J Pathol. 2012;181(4):1426-35. https://doi.org/10.1016/j.ajpath.2012.06.033
https://doi.org/10.1016/j.ajpath.2012.06... . Like a vicious cycle, Aβ can trigger the tau protein conversion to a toxic state, and as a feedback loop, it will also enhance the Aβ itself⁶²62 Bloom GS. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014;71(4):505-8. https://doi.org/10.1001/jamaneurol.2013.5847
https://doi.org/10.1001/jamaneurol.2013.... .

Although cerebral oxidative damage is a part of aging and neurodegenerative diseases, OS and inflammatory processes are also environmentally driven risk factors that were found to interact with apolipoprotein E (ApoE)-encoding, the APOE-gene that plays a significant role in the neuropathology course of AD and leads to a susceptibility of AD development and progression⁷⁴74 Lahiri DK, Maloney B. Genomics of brain aging: Apolipoprotein E. In: Squire LR, Bloom FE, Spitzer NC, Gage F, eds. Encyclopedia of neuroscience. Oxford: Academic Press; 2009. p. 685-93.. In AD, Aβ which was transported into cells contributing to ROS, which then induced the cytokine response interleukin-6 (IL-6) and simultaneously with activation of NF-kB in the nucleus will activate the expression of the APOE-gene¹³13 Fischer R, Maier O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev. 2015;2015:e610813. https://doi.org/10.1155/2015/610813
https://doi.org/10.1155/2015/610813... ,⁷⁴74 Lahiri DK, Maloney B. Genomics of brain aging: Apolipoprotein E. In: Squire LR, Bloom FE, Spitzer NC, Gage F, eds. Encyclopedia of neuroscience. Oxford: Academic Press; 2009. p. 685-93.,⁷⁵75 Lahiri DK, Sambamurti K, Bennett DA. Apolipoprotein gene and its interaction with the environmentally driven risk factors: molecular, genetic and epidemiological studies of Alzheimer’s disease. Neurobiol Aging. 2004;25(5):651-60. https://doi.org/10.1016/j.neurobiolaging.2003.12.024
https://doi.org/10.1016/j.neurobiolaging... . Neurochemically, ApoE was co-localized with AD neuropathological lesions, where plaques and tangles were deposited, and an increase of ApoE mRNA in astrocytes was found in the hippocampus and other regions of the brain that had degenerated neuron cell bodies or synaptic remodeling; this event indicates the occurrence of lipid uptake in the neurodegeneration process of AD⁷⁴74 Lahiri DK, Maloney B. Genomics of brain aging: Apolipoprotein E. In: Squire LR, Bloom FE, Spitzer NC, Gage F, eds. Encyclopedia of neuroscience. Oxford: Academic Press; 2009. p. 685-93.,⁷⁶76 Kanekiyo T, Xu H, Bu G. ApoE and Aβ in Alzheimer’s disease: accidental encounters or partners? Neuron. 2014;81(4):740-54. https://doi.org/10.1016/j.neuron.2014.01.045
https://doi.org/10.1016/j.neuron.2014.01... .

The APOE-gene is one of the strongest genetic risk loci associated with late-onset AD (LOAD), increasing the risk of events 3 to 15-fold⁷⁷77 Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet. 2019;51(3):404-13. https://doi.org/10.1038/s41588-018-0311-9
https://doi.org/10.1038/s41588-018-0311-... ,⁷⁸78 Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106-18. https://doi.org/10.1038/nrneurol.2012.263
https://doi.org/10.1038/nrneurol.2012.26... . ApoE is a 299-amino-acid protein polymorphic that is synthesized and secreted mainly in the liver and brain by astrocytes, oligodendrocytes, activated microglia, and ependymal layer cells, and a lower level of expression was also found in central nervous system (CNS) neurons; functionally as cholesterol transporter protein among the various cells including in the brain⁷⁴74 Lahiri DK, Maloney B. Genomics of brain aging: Apolipoprotein E. In: Squire LR, Bloom FE, Spitzer NC, Gage F, eds. Encyclopedia of neuroscience. Oxford: Academic Press; 2009. p. 685-93.,⁷⁹79 Keene CD, Cudaback E, Li X, Montine KS, Montine TJ. Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer’s disease. Curr Opin Neurobiol. 2011;21(6):920-8. https://doi.org/10.1016/j.conb.2011.08.002
https://doi.org/10.1016/j.conb.2011.08.0... ,⁸⁰80 Verghese PB, Castellano JM, Holtzman DM. Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol. 2011;10(3):241-52. https://doi.org/10.1016/S1474-4422(10)70325-2
https://doi.org/10.1016/S1474-4422(10)70... . Among three alleles of APOE-gene (ε2, ε3, and ε4) that encode three isoform proteins, the ε4 allele plays a major role as a susceptibility factor of AD development⁷⁹79 Keene CD, Cudaback E, Li X, Montine KS, Montine TJ. Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer’s disease. Curr Opin Neurobiol. 2011;21(6):920-8. https://doi.org/10.1016/j.conb.2011.08.002
https://doi.org/10.1016/j.conb.2011.08.0... ,⁸¹81 Nishimura M, Satoh M, Matsushita K, Nomura F. How proteomic ApoE serotyping could impact Alzheimer’s disease risk assessment: genetic testing by proteomics. Expert Rev Proteomics. 2014;11(4):405-7. https://doi.org/10.1586/14789450.2014.936390
https://doi.org/10.1586/14789450.2014.93... . Histopathological studies also showed that the ε4 allele was associated with the amount of neuritic plaque and NFTs, suggesting its role in mediating AD neuropathology accumulation in line with clinical changes⁷⁴74 Lahiri DK, Maloney B. Genomics of brain aging: Apolipoprotein E. In: Squire LR, Bloom FE, Spitzer NC, Gage F, eds. Encyclopedia of neuroscience. Oxford: Academic Press; 2009. p. 685-93.. APOE ε4 has neurotoxic properties, promotes fibrillogenesis, and has been found to be associated with increased risk and accelerated age-onset of AD⁸²82 Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019;15(9):501-18. https://doi.org/10.1038/s41582-019-0228-7
https://doi.org/10.1038/s41582-019-0228-... . The interaction circle of Aβ, ApoE, cholesterol, and APP will form a cascade of a series of events in the pathogenesis of AD along with molecular changes of OS (Figure 1).

Brain-derived neurotrophic factor interplay with oxidative stress and its potential as Alzheimer’s disease biomarker

Overview of brain-derived neurotrophic factor in neurodegenerative diseases

BDNF is a neurotrophin synthesized by neurons and has a key role in the development and maturation of the nervous system, including neuronal survival, restoration, and differentiation, besides synaptic function, axonal and dendritic growth, and energy requirements in carrying out nerve functions²⁴24 Balietti M. Blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease. In: Martin CR, Preedy VR, eds. Diagnosis and management in dementia. Academic Press; 2020. p. 281-96.,⁸³83 Yang J, Siao CJ, Nagappan G, Marinic T, Jing D, McGrath K, et al. Neuronal release of proBDNF. Nat Neurosci. 2009;12(2):113-5. https://doi.org/10.1038/nn.2244
https://doi.org/10.1038/nn.2244... ,⁸⁴84 Hu Y, Russek SJ. BDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulation. J Neurochem. 2008;105(1):1-17. https://doi.org/10.1111/j.1471-4159.2008.05237.x
https://doi.org/10.1111/j.1471-4159.2008... . BDNF was initially synthesized as a propeptide (proBDNF) in the lumen of the endoplasmic reticulum, together with the signal peptide. The proBDNF inside the trans-Golgi network (TGN) will undergo a cleavage process dividing the active peptides of mature-BDNF (mBDNF; pre-domain) from the pro-domains site by the works of proteolytic enzyme intracellular proprotein convertases (PCs) — furin and PC1 to PC7 — that can pass through two types of vesicles in TGN, namely through vesicles for consecutive release (VCR) of the consecutive secretion pathway or through secretory granules (SG) of the regulated secretion pathway; meanwhile, if it reaches the extracellular matrix before the intracellular cleavage, the proBDNF is cleaved by extracellular proteases, plasmin (tissue plasminogen activator/tPA), and matrix metalloproteases (Figure 2)¹⁵15 Wang M, Xie Y, Qin D. Proteolytic cleavage of proBDNF to mBDNF in neuropsychiatric and neurodegenerative diseases. Brain Res Bull. 2021;166:172-84. https://doi.org/10.1016/j.brainresbull.2020.11.005
https://doi.org/10.1016/j.brainresbull.2... ,⁸⁵85 Lessmann V, Brigadski T. Mechanisms, locations, and kinetics of synaptic BDNF secretion: an update. Neurosci Res. 2009;65(1):11-22. https://doi.org/10.1016/j.neures.2009.06.004
https://doi.org/10.1016/j.neures.2009.06... .

Not all proBDNF is transformed into mBDNF, some are not processed under proteolytic cleavage and secreted exocytosis by VCR or SG directly to the extracellular²⁴24 Balietti M. Blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease. In: Martin CR, Preedy VR, eds. Diagnosis and management in dementia. Academic Press; 2020. p. 281-96.. The mBDNF binds to the high-affinity tropomyosin-related receptor kinase B (TrkB) and fosters several benefits as the consolidation of long-term potentiation (LTP) involved in neural plasticity; it triggers neural stem cells survival and differentiation and spine growth; helps synaptogenesis and synaptic maturation; increases glutamate release; decreases neuronal GABAergic (gamma-aminobutyric acidergic) excitability; and helps energetic challenge adaptation and stress resistance²⁴24 Balietti M. Blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease. In: Martin CR, Preedy VR, eds. Diagnosis and management in dementia. Academic Press; 2020. p. 281-96.,⁸⁶86 Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci. 2015;11(6):1164-78. https://doi.org/10.5114/aoms.2015.56342
https://doi.org/10.5114/aoms.2015.56342... . In addition, the pro-domains that have been separated from mBDNF can be activated by binding to GluN2B containing N-methyl-D-aspartate receptors (NMDAR), triggering a reduction in dendritic spine density and growth cone retraction, and facilitating long-term depression (LTD). The proBDNF, which is not converted into mBDNF, also facilitates LTD by binding to the p75NTR (p75 neurotrophin receptor) and sortilin complexes, which induces apoptosis, growth cone retraction, suppresses spine pruning, and decreases glutamate release²⁴24 Balietti M. Blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease. In: Martin CR, Preedy VR, eds. Diagnosis and management in dementia. Academic Press; 2020. p. 281-96.,⁸⁶86 Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Arch Med Sci. 2015;11(6):1164-78. https://doi.org/10.5114/aoms.2015.56342
https://doi.org/10.5114/aoms.2015.56342... .

Je et al. proposed proBDNF and mBDNF as reward and punishment signaling models, respectively, for synaptic elimination of neuromuscular junctions (NMJs) based on in vivo experiments by inhibiting proteolytic conversion to mBDNF. Thus, the proBDNF would accelerate the presynaptic elimination of axon terminals through p75NTR activation, and, in contrast, when p75NTR and sortilin signaling was inhibited, it would attenuate and delay the synaptic elimination process⁸⁷87 Je HS, Yang F, Ji Y, Potluri S, Fu XQ, Luo ZG, et al. ProBDNF and mature BDNF as punishment and reward signals for synapse elimination at mouse neuromuscular junctions. J Neurosci. 2013;33(24):9957-62. https://doi.org/10.1523/JNEUROSCI.0163-13.2013
https://doi.org/10.1523/JNEUROSCI.0163-1... . Even elevated plasma levels of proBDNF and excessive proBDNF in the brain can exhibit stereotypical behavior, impaired social interaction, hyperactivity, and increased stress response⁸⁸88 You H, Mizui T, Kiyosue K, Takao K, Miyakawa T, Kato K, et al. Inhibiting proBDNF to mature BDNF conversion leads to autism-like phenotypes in vivo. bioRxiv. 2020;149104. https://doi.org/10.1101/2020.06.12.149104
https://doi.org/10.1101/2020.06.12.14910... . The role of BDNF in neurogenesis and synaptic plasticity also illustrates the susceptibility that arises when the production of mBDNF in carrying out its functions is inadequate, and this is reflected in a significant decrease in BDNF levels in neurological diseases such as AD and other types of dementia, Parkinson’s disease, epilepsy, Huntington’s disease, as well as neurobehavior disorders such as schizophrenia, autism, depression, and social avoidance⁸⁴84 Hu Y, Russek SJ. BDNF and the diseased nervous system: a delicate balance between adaptive and pathological processes of gene regulation. J Neurochem. 2008;105(1):1-17. https://doi.org/10.1111/j.1471-4159.2008.05237.x
https://doi.org/10.1111/j.1471-4159.2008... ,⁸⁹89 Lee JG, Shin BS, You YS, Kim JE, Yoon SW, Jeon DW, et al. Decreased serum brain-derived neurotrophic factor levels in elderly Korean with dementia. Psychiatry Investig. 2009;6(4):299-305. https://doi.org/10.4306/pi.2009.6.4.299
https://doi.org/10.4306/pi.2009.6.4.299... ,⁹⁰90 Dulka BN, Ford EC, Lee MA, Donnell NJ, Goode TD, Prosser R, et al. Proteolytic cleavage of proBDNF into mature BDNF in the basolateral amygdala is necessary for defeat-induced social avoidance. Learn Mem. 2016;23(4):156-60. https://doi.org/10.1101/lm.040253.115
https://doi.org/10.1101/lm.040253.115... .

The condition of impaired cognitive function and memory formation in AD is not far from the area of the brain that supports its function; the interconnection between the entorhinal cortex (EC) and the hippocampus, and BDNF also influences the processes within this learning pathway. In these two areas, there is information flow that forms organized circuit loops, corticohippocampal and intrahippocampal connections that play a role in the learning process; and brain synaptic plasticity has a role in learning that includes sensory experiences and adaptive processes to spatial, episodic, social, and contextual memory⁹¹91 Basu J, Siegelbaum SA. The corticohippocampal circuit, synaptic plasticity, and memory. Cold Spring Harb Perspect Biol. 2015;7(11):a021733. https://doi.org/10.1101/cshperspect.a021733
https://doi.org/10.1101/cshperspect.a021... ,⁹²92 van Strien NM, Cappaert NLM, Witter MP. The anatomy of memory: an interactive overview of the parahippocampal-hippocampal network. Nat Rev Neurosci. 2009;10(4):272-82. https://doi.org/10.1038/nrn2614
https://doi.org/10.1038/nrn2614... . These neoclassical pathways of the corticohippocampal circuit start from the entry of glutamatergic input from the superficial EC in the area that carries nonspatial sensory information (lateral EC/LEC) and spatial information (medial EC/MEC)⁹¹91 Basu J, Siegelbaum SA. The corticohippocampal circuit, synaptic plasticity, and memory. Cold Spring Harb Perspect Biol. 2015;7(11):a021733. https://doi.org/10.1101/cshperspect.a021733
https://doi.org/10.1101/cshperspect.a021... ,⁹²92 van Strien NM, Cappaert NLM, Witter MP. The anatomy of memory: an interactive overview of the parahippocampal-hippocampal network. Nat Rev Neurosci. 2009;10(4):272-82. https://doi.org/10.1038/nrn2614
https://doi.org/10.1038/nrn2614... . Grid cells on EC in layers II (LII) and layers III (LIII) then carry information for processing in the hippocampus on several parallel circuits: CA1 pyramidal neurons via trisynaptic paths (EC LII to the dentate gyrus, then to CA3 and towards CA1) or monosynaptic paths (EC LIII to CA1); CA1 also gets direct monosynaptic projection from MEC LII; besides, CA2 gets direct input from LII MEC and LEC before going to the dendritic domains of stratum oriens/radiatum CA1 which overlaps with the input from CA3 to CA1; to complete the circuit loop, the hippocampus performs a back-projection to the deep EC⁹¹91 Basu J, Siegelbaum SA. The corticohippocampal circuit, synaptic plasticity, and memory. Cold Spring Harb Perspect Biol. 2015;7(11):a021733. https://doi.org/10.1101/cshperspect.a021733
https://doi.org/10.1101/cshperspect.a021... ,⁹³93 Chevaleyre V, Siegelbaum SA. Strong CA2 pyramidal neuron synapses define a powerful disynaptic cortico-hippocampal loop. Neuron. 2010;66(4):560-72. https://doi.org/10.1016/j.neuron.2010.04.013
https://doi.org/10.1016/j.neuron.2010.04... ,⁹⁴94 Piskorowski RA, Chevaleyre V. Synaptic integration by different dendritic compartments of hippocampal CA1 and CA2 pyramidal neurons. Cell Mol Life Sci. 2012;69(1):75-88. https://doi.org/10.1007/s00018-011-0769-4
https://doi.org/10.1007/s00018-011-0769-... .

BDNF performs LTP modulation, which is useful in preserving synaptic plasticity function in the Schaffer collateral terminals – CA1 area of the hippocampus⁹⁵95 Xu B, Gottschalk W, Chow A, Wilson RI, Schnell E, Zang K, et al. The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J Neurosci. 2000;20(18):6888-97. https://doi.org/10.1523/JNEUROSCI.20-18-06888.2000
https://doi.org/10.1523/JNEUROSCI.20-18-... –⁹⁷97 Lin PY, Kavalali ET, Monteggia LM. Genetic dissection of presynaptic and postsynaptic BDNF-TrkB signaling in synaptic efficacy of CA3-CA1 synapses. Cell Rep. 2018;2496):1550-61. https://doi.org/10.1016/j.celrep.2018.07.020
https://doi.org/10.1016/j.celrep.2018.07... . Although previously found that postsynaptic and interneuronal transmissions have the potential to be BDNF locus of action, a later study observed that BDNF exclusively enhances transmitter release on TrkB receptors, not p75NTR, on presynaptic CA3 afferent neurons or interneurons for synaptic LTP modulation in the CA1 region⁹⁵95 Xu B, Gottschalk W, Chow A, Wilson RI, Schnell E, Zang K, et al. The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J Neurosci. 2000;20(18):6888-97. https://doi.org/10.1523/JNEUROSCI.20-18-06888.2000
https://doi.org/10.1523/JNEUROSCI.20-18-... –⁹⁷97 Lin PY, Kavalali ET, Monteggia LM. Genetic dissection of presynaptic and postsynaptic BDNF-TrkB signaling in synaptic efficacy of CA3-CA1 synapses. Cell Rep. 2018;2496):1550-61. https://doi.org/10.1016/j.celrep.2018.07.020
https://doi.org/10.1016/j.celrep.2018.07... . Thus, BDNF signaling is not directly involved in the biochemical changes of LTP in the postsynaptic neurons but by modulation of repetitive exocytotic events presynaptically that indirectly modify LTP response postsynaptically⁹⁵95 Xu B, Gottschalk W, Chow A, Wilson RI, Schnell E, Zang K, et al. The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J Neurosci. 2000;20(18):6888-97. https://doi.org/10.1523/JNEUROSCI.20-18-06888.2000
https://doi.org/10.1523/JNEUROSCI.20-18-... –⁹⁷97 Lin PY, Kavalali ET, Monteggia LM. Genetic dissection of presynaptic and postsynaptic BDNF-TrkB signaling in synaptic efficacy of CA3-CA1 synapses. Cell Rep. 2018;2496):1550-61. https://doi.org/10.1016/j.celrep.2018.07.020
https://doi.org/10.1016/j.celrep.2018.07... . In contrast to LTP, the LTD process in the hippocampus is due to activation of proBDNF-p75NTR signaling localized in dendritic spines and CA1 afferent terminals. Furthermore, LTD activity is uniquely due to decreased expression of NMDAR subunit 2B, so deletion of the p75NTR receptor selectively disrupts NMDAR-dependent LTD without affecting LTP synaptic plasticity, both proBDNF and BDNF acting bidirectionally⁹⁸98 Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, et al. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci. 2005;8(8):1069-77. https://doi.org/10.1038/nn1510
https://doi.org/10.1038/nn1510... .

How oxidative stress affects brain-derived neurotrophic factor and the factor as a potential biomarker of Alzheimer’s disease

BDNF expressed in the CNS and blood has been found to be involved in the neuropathology of various neurodegenerative diseases, including AD. An imbalance or lack of mBDNF causes impaired neuronal plasticity that underlies a hypothesis of the strategy to optimize mBDNF transformation as a prospective AD therapy target¹⁵15 Wang M, Xie Y, Qin D. Proteolytic cleavage of proBDNF to mBDNF in neuropsychiatric and neurodegenerative diseases. Brain Res Bull. 2021;166:172-84. https://doi.org/10.1016/j.brainresbull.2020.11.005
https://doi.org/10.1016/j.brainresbull.2... ,¹⁶16 Song JH, Yu JT, Tan L. Brain-derived neurotrophic factor in Alzheimer’s disease: risk, mechanisms, and therapy. Mol Neurobiol. 2015;52(3):1477-93. https://doi.org/10.1007/s12035-014-8958-4
https://doi.org/10.1007/s12035-014-8958-... . BDNF stimulates the non-amyloidogenic pathway of APP as a protective factor for AD, but OS leads to decreased BDNF levels and, in turn, leads to increased Aβ, which worsens AD progression⁹⁹99 Rohe M, Synowitz M, Glass R, Paul SM, Nykjaer A, Willnow TE. Brain-derived neurotrophic factor reduces amyloidogenic processing through control of SORLA gene expression. J Neurosci. 2009;29(49):15472-8. https://doi.org/10.1523/JNEUROSCI.3960-09.2009
https://doi.org/10.1523/JNEUROSCI.3960-0... ,¹⁰⁰100 Kapczinski F, Frey BN, Andreazza AC, Kauer-Sant’Anna M, Cunha ABM, Post RM. Increased oxidative stress as a mechanism for decreased BDNF levels in acute manic episodes. Braz J Psychiatry. 2008;30(3):243-5. https://doi.org/10.1590/s1516-44462008000300011
https://doi.org/10.1590/s1516-4446200800... .

BDNF was found to potentially protect against neurotoxicity induced by Aβ and restore the nerve alteration induced by Aβ 1-42¹⁰¹101 Amidfar M, Oliveira J, Kucharska E, Budni J, Kim YK. The role of CREB and BDNF in neurobiology and treatment of Alzheimer’s disease. Life Sci. 2020;257:118020. https://doi.org/10.1016/j.lfs.2020.118020
https://doi.org/10.1016/j.lfs.2020.11802... ,¹⁰²102 Aliaga E, Silhol M, Bonneau N, Maurice T, Arancibia S, Tapia-Arancibia L. Dual response of BDNF to sublethal concentrations of β-amyloid peptides in cultured cortical neurons. Neurobiol Dis. 2010;37(1):208-17. https://doi.org/10.1016/j.nbd.2009.10.004
https://doi.org/10.1016/j.nbd.2009.10.00... . Vice versa, downregulation of BDNF expression caused by Aβ lead to cognitive dysfunction and loss of memory, as BDNF is involved in brain areas of the hippocampus, cortical and basal forebrain function for learning, memory, and higher cognitive function¹⁰¹101 Amidfar M, Oliveira J, Kucharska E, Budni J, Kim YK. The role of CREB and BDNF in neurobiology and treatment of Alzheimer’s disease. Life Sci. 2020;257:118020. https://doi.org/10.1016/j.lfs.2020.118020
https://doi.org/10.1016/j.lfs.2020.11802... –¹⁰⁵105 Zussy C, Brureau A, Keller E, Marchal S, Blayo C, Delair B, et al. Alzheimer’s disease related markers, cellular toxicity and behavioral deficits induced six weeks after oligomeric amyloid-β peptide injection in rats. PLoS One. 2013;8(1):e53117. https://doi.org/10.1371/journal.pone.0053117
https://doi.org/10.1371/journal.pone.005... . Aβ plaques are involved in impaired BDNF synthesis and transduction of neurotransmitters, leading to blockage of synapse and accelerated nerve degeneration that is also underlying AD etiology⁸⁹89 Lee JG, Shin BS, You YS, Kim JE, Yoon SW, Jeon DW, et al. Decreased serum brain-derived neurotrophic factor levels in elderly Korean with dementia. Psychiatry Investig. 2009;6(4):299-305. https://doi.org/10.4306/pi.2009.6.4.299
https://doi.org/10.4306/pi.2009.6.4.299... ,¹⁰⁶106 Mattson MP, Maudsley S, Martin B. BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders. Trends Neurosci. 2004;27(10):589-94. https://doi.org/10.1016/j.tins.2004.08.001
https://doi.org/10.1016/j.tins.2004.08.0... . Quantification of BDNF mRNA levels in AD brain tissue showed a 3.4-fold decrease compared to the control group²³23 Holsinger RM, Schnarr J, Henry P, Castelo VT, Fahnestock M. Quantitation of BDNF mRNA in human parietal cortex by competitive reverse transcription-polymerase chain reaction: decreased levels in Alzheimer’s disease. Brain Res Mol Brain Res. 2000;76(2):347-54. https://doi.org/10.1016/s0169-328x(00)00023-1
https://doi.org/10.1016/s0169-328x(00)00... . ProBDNF buildup in mouse models indicates decreased brain volume, reduced dendritic arborization, impaired synaptic transmission, and neuronal plasticity⁸⁸88 You H, Mizui T, Kiyosue K, Takao K, Miyakawa T, Kato K, et al. Inhibiting proBDNF to mature BDNF conversion leads to autism-like phenotypes in vivo. bioRxiv. 2020;149104. https://doi.org/10.1101/2020.06.12.149104
https://doi.org/10.1101/2020.06.12.14910... . Lu et al. described the activity of the mature neurotrophin and its precursor proBDNF at their respective receptors as “yin and yang” action as they play opposite roles in modulating neuronal synaptic plasticity and survival¹⁰⁷107 Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nat Rev Neurosci. 2005;6(8):603-14. https://doi.org/10.1038/nrn1726
https://doi.org/10.1038/nrn1726... .

Increased BDNF levels are correlated with an antioxidant defense mechanism against OS¹⁰⁸108 Mattson MP, Duan W, Maswood N. How does the brain control lifespan? Ageing Res Rev. 2002;1(2):155-65. https://doi.org/10.1016/s1568-1637(01)00003-4
https://doi.org/10.1016/s1568-1637(01)00... . OS roles in AD neuropathology lead to decreased BDNF levels by suppressing and reducing cAMP response element-binding (CREB) expression and its phosphorylated-CREB (pCREB) content, increased nuclear factor-kappa B (NF-kB) DNA-binding activity, and energy depletion (Figure 1)¹⁷17 Zou J, Crews F. CREB and NF-kappaB transcription factors regulate sensitivity to excitotoxic and oxidative stress induced neuronal cell death. Cell Mol Neurobiol. 2006;26(4-6):385-405. https://doi.org/10.1007/s10571-006-9045-9
https://doi.org/10.1007/s10571-006-9045-... ,¹⁸18 Wu A, Ying Z, Gomez-Pinilla F. The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition. Eur J Neurosci. 2004;1997):1699-707. https://doi.org/10.1111/j.1460-9568.2004.03246.x
https://doi.org/10.1111/j.1460-9568.2004... . CREB is a major mediator and regulator of the BDNF-induced gene expression response through the regulation of its transcription by the binding of pCREB to a specific sequence in the BDNF promoter¹⁰⁹109 Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM, Greenberg ME. CREB: a major mediator of neuronal neurotrophin responses. Neuron. 1997;19(5):1031-47. https://doi.org/10.1016/s0896-6273(00)80395-5
https://doi.org/10.1016/s0896-6273(00)80... ,¹¹⁰110 Wang H, Xu J, Lazarovici P, Quirion R, Zheng W. cAMP response element-binding protein (CREB): a possible signaling molecule link in the pathophysiology of schizophrenia. Front Mol Neurosci. 2018;11:255. https://doi.org/10.3389/fnmol.2018.00255
https://doi.org/10.3389/fnmol.2018.00255... . CREB as a major neurotrophin response regulator in mature neurons can trigger neurotrophins to induce the expression of regulatory regions in CREB-regulated genes that mediate the long-lasting effects of neurotrophin activity on synaptic function. Through this CREB-dependent gene expression, BDNF can influence and consolidate synaptic strength¹⁰⁹109 Finkbeiner S, Tavazoie SF, Maloratsky A, Jacobs KM, Harris KM, Greenberg ME. CREB: a major mediator of neuronal neurotrophin responses. Neuron. 1997;19(5):1031-47. https://doi.org/10.1016/s0896-6273(00)80395-5
https://doi.org/10.1016/s0896-6273(00)80... . From the genetic perspective, the presence of BDNF genetic polymorphism at codon 66, the Met66 allele, was also significantly associated with cognitive impairment as MCI progressed to AD and interacted with ApoE 4¹¹¹111 Diniz BS, Teixeira AL. Brain-derived neurotrophic factor and Alzheimer’s disease: physiopathology and beyond. Neuromolecular Med. 2011;13(4):217-22. https://doi.org/10.1007/s12017-011-8154-x
https://doi.org/10.1007/s12017-011-8154-... ,¹¹²112 Tsai SJ, Hong CJ, Liu HC, Liu TY, Hsu LE, Lin CH. Association analysis of brain-derived neurotrophic factor Val66Met polymorphisms with Alzheimer’s disease and age of onset. Neuropsychobiology. 2004;49(1):10-2. https://doi.org/10.1159/000075332
https://doi.org/10.1159/000075332... .

By the fact that OS interplays with BDNF in neuropathology and progression of AD, BDNF levels are a potential biomarker for diagnosis and progressivity follow-up. No molecule has been proven to be conclusive for AD diagnosis at the pre-symptomatic stage until today²⁴24 Balietti M. Blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease. In: Martin CR, Preedy VR, eds. Diagnosis and management in dementia. Academic Press; 2020. p. 281-96.. However, there are several possible molecular biomarkers of AD associated with its progressivity: BDNF and Pittsburgh compound B positron emission tomography (PET) in the brain; Aβ1-42, neurogranin, and total and phosphorylated tau protein in cerebrospinal fluid (CSF); and examination of miR-107 mRNA, plasma neurofilament light, platelet amyloid precursor protein isoform ratio, lipid peroxidation products, and vascular cell adhesion molecule-1 in blood²⁴24 Balietti M. Blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease. In: Martin CR, Preedy VR, eds. Diagnosis and management in dementia. Academic Press; 2020. p. 281-96.. Based on the biomarker effectiveness for an early AD diagnosis, it is necessary to consider the ease of examination, the availability of extensive facilities, and invasiveness minimization. Thus, the use of circulating BDNF through peripheral blood fulfills the effectiveness of this biomarker; however, further validation in properly wide longitudinal studies comparing to current consolidated biomarkers of AD should be conducted to include BDNF as a valid molecular biomarker. In the future, BDNF may possibly be added as a newly available biomarker to the amyloid-tau-neurodegeneration (ATN) system developed by Jack Jr et al. in the National Institute on Aging and Alzheimer’s Association (NIA-AA) Research Framework that is widely used to diagnose AD that, not only focuses on cognitive staging, but also on any biomarkers changes in the AD continuum¹¹³113 Jack Jr CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14(4):535-62. https://doi.org/10.1016/j.jalz.2018.02.018
https://doi.org/10.1016/j.jalz.2018.02.0... . The new AD biomarker could contribute to defining AD severity in the AT(N) system, as N covers up all neurodegenerative or neuronal injury biomarkers. B sides, in the NIA-AA framework, it is stated that new biomarker groups could be added when it is available, without ruling out A (Aβ) and T (pathologic tau) as the unique neuropathologic biomarker to diagnose AD and exclude other causes of dementia. Circulating BDNF levels reflect the progression of AD staging as an early compensatory increase in amnestic-MCI (aMCI) and early-stage AD, followed by a decrease in the late-stage AD²⁴24 Balietti M. Blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease. In: Martin CR, Preedy VR, eds. Diagnosis and management in dementia. Academic Press; 2020. p. 281-96.,¹¹⁴114 Laske C, Stransky E, Leyhe T, Eschweiler GW, Wittorf A, Richartz E, et al. Stage-dependent BDNF serum concentrations in Alzheimer’s disease. J Neural Transm (Vienna). 2006;113(9):1217-24. https://doi.org/10.1007/s00702-005-0397-y
https://doi.org/10.1007/s00702-005-0397-... ,¹¹⁵115 Angelucci F, Spalletta G, di Iulio F, Ciaramella A, Salani F, Colantoni L, et al. Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients are characterized by increased BDNF serum levels. Curr Alzheimer Res. 2010;7(1):15-20. https://doi.org/10.2174/156720510790274473
https://doi.org/10.2174/1567205107902744... . The decrease in BDNF levels may also be associated with cognitive deterioration in healthy elderly; however, a decrease in BDNF levels in AD was significantly lower⁸⁹89 Lee JG, Shin BS, You YS, Kim JE, Yoon SW, Jeon DW, et al. Decreased serum brain-derived neurotrophic factor levels in elderly Korean with dementia. Psychiatry Investig. 2009;6(4):299-305. https://doi.org/10.4306/pi.2009.6.4.299
https://doi.org/10.4306/pi.2009.6.4.299... ,¹¹⁶116 Forlenza OV, Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonça VA, et al. Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment. World J Biol Psychiatry. 2010;11(6):774-80. https://doi.org/10.3109/15622971003797241
https://doi.org/10.3109/1562297100379724... ,¹¹⁷117 Gunstad J, Benitez A, Smith J, Glickman E, Spitznagel MB, Alexander T, et al. Serum brain-derived neurotrophic factor is associated with cognitive function in healthy older adults. J Geriatr Psychiatry Neurol. 2008;21(3):166-70. https://doi.org/10.1177/0891988708316860
https://doi.org/10.1177/0891988708316860... . In addition to the usefulness of circulating BDNF as an AD biomarker, Li et al. also show that central BDNF levels from CSF can be an independent predictor to follow the progression of aMCI to AD and signs of cognitive decline¹¹⁸118 Li G, Peskind ER, Millard SP, Chi P, Sokal I, Yu CE, et al. Cerebrospinal fluid concentration of brain-derived neurotrophic factor and cognitive function in non-demented subjects. PLoS One. 2009;4(5):e5424. https://doi.org/10.1371/journal.pone.0005424
https://doi.org/10.1371/journal.pone.000... .

BDNF is mainly produced by neurons and glial cells in the CNS; however, BDNF can also be synthesized from peripheral sources by vascular endothelial cells, lymphocytes, smooth cells, and activated macrophages, while platelets function as the main storage pool for BDNF²⁴24 Balietti M. Blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease. In: Martin CR, Preedy VR, eds. Diagnosis and management in dementia. Academic Press; 2020. p. 281-96.,¹¹⁹119 Pan W, Banks WA, Fasold MB, Bluth J, Kastin AJ. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology. 1998;37(12):1553-61. https://doi.org/10.1016/s0028-3908(98)00141-5
https://doi.org/10.1016/s0028-3908(98)00... ,¹²⁰120 Karege F, Bondolfi G, Gervasoni N, Schwald M, Aubry JM, Bertschy G. Low brain-derived neurotrophic factor (BDNF) levels in serum of depressed patients probably results from lowered platelet BDNF release unrelated to platelet reactivity. Biol Psychiatry. 2005;57(9):1068-72. https://doi.org/10.1016/j.biopsych.2005.01.008
https://doi.org/10.1016/j.biopsych.2005.... . Although studies on animals and humans have shown a correlation between blood BDNF levels, brain BDNF levels, and the cerebral phenomenon, further research is still needed to determine whether blood BDNF levels accurately and precisely reflect their levels in the brain²⁴24 Balietti M. Blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease. In: Martin CR, Preedy VR, eds. Diagnosis and management in dementia. Academic Press; 2020. p. 281-96.,¹²¹121 Nakahashi T, Fujimura H, Altar CA, Li J, Kambayashi J, Tandon NN, et al. Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBS Lett. 2000;470(2):113-7. https://doi.org/10.1016/s0014-5793(00)01302-8
https://doi.org/10.1016/s0014-5793(00)01... . There is also a difficulty in choosing the use of circulating BDNF — between serum or plasma BDNF — because different results may be obtained from these two matrices; BDNF serum levels are 200 times higher than BDNF plasma levels because they reflect the amount of stored BDNF in circulating platelets released during clotting²⁴24 Balietti M. Blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease. In: Martin CR, Preedy VR, eds. Diagnosis and management in dementia. Academic Press; 2020. p. 281-96.,¹²²122 Balietti M, Giuli C, Conti F. Peripheral blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease: are there methodological biases? Mol Neurobiol. 2018;55(8):6661-72. https://doi.org/10.1007/s12035-017-0866-y
https://doi.org/10.1007/s12035-017-0866-... . However, both can also be important biomarkers because serum levels represent a long-term storage pool, whereas plasma levels represent bioactive forms²⁴24 Balietti M. Blood brain-derived neurotrophic factor as a biomarker of Alzheimer’s disease. In: Martin CR, Preedy VR, eds. Diagnosis and management in dementia. Academic Press; 2020. p. 281-96..

BDNF levels used as a biomarker for AD diagnosis and progressivity follow-up might have a limitation in its specificity because changes in BDNF, as previously described, also occur in several other neurodegenerative and neurobehavior diseases, although not as significant as in AD. OS and all AD-related neuropathology cascades could either influence or be influenced by BDNF, and changes in one system will affect other systems, all of which are involved in the neurodegenerative cascade of AD¹¹¹111 Diniz BS, Teixeira AL. Brain-derived neurotrophic factor and Alzheimer’s disease: physiopathology and beyond. Neuromolecular Med. 2011;13(4):217-22. https://doi.org/10.1007/s12017-011-8154-x
https://doi.org/10.1007/s12017-011-8154-... . Further research is needed regarding the use of BDNF as an AD biomarker, including (Figure 3):

• The diagnostic value and its standard cut-off for each AD stage;

• The best circulation of BDNF, whether plasma or serum;

• The limitation compared to the current gold-standard for diagnosis,

• The possibility for routine assessment to define AD progression; and

• The potential of its use for target therapy.

As an antioxidant happens to be a natural counter for OS, its use as a preventive, therapeutic approach might also be considered to increase BDNF levels. Simple approaches, such as diet modification, can be taken to avoid dietary pro-oxidants and increase natural antioxidant consumption. A study found that a chronic exposure to pro-oxidant substances (e.g., organophosphates in agriculture products) can trigger OS that significantly reduces mRNA expression and protein levels of BDNF¹²³123 Jain S, Banerjee BD, Ahmed RS, Arora VK, Mediratta PK. Possible role of oxidative stress and brain derived neurotrophic factor in triazophos induced cognitive impairment in rats. Neurochem Res. 2013;38(10):2136-47. https://doi.org/10.1007/s11064-013-1122-0
https://doi.org/10.1007/s11064-013-1122-... . High-fat diet consumption also triggers oxidative damage that reduces BDNF protein and mRNA levels and their downstream effectors (synapsin I and CREB)¹⁸18 Wu A, Ying Z, Gomez-Pinilla F. The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition. Eur J Neurosci. 2004;1997):1699-707. https://doi.org/10.1111/j.1460-9568.2004.03246.x
https://doi.org/10.1111/j.1460-9568.2004... . The provision of antioxidants can significantly prevent these effects and perform reverse protein oxidation events, and normalizing BDNF levels results in improvements in synaptic plasticity and cognitive function¹⁸18 Wu A, Ying Z, Gomez-Pinilla F. The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition. Eur J Neurosci. 2004;1997):1699-707. https://doi.org/10.1111/j.1460-9568.2004.03246.x
https://doi.org/10.1111/j.1460-9568.2004... . An experimental study by Handajani et al. also found the benefit of natural antioxidants by consuming 100 grams of Tempeh (soy fermented with Rhizopus fungi) per day for six months, which increased the global cognitive scores of MCI elderly, higher than the control¹²⁴124 Handajani YS, Turana Y, Yogiara Y, Widjaja NT, Sani TP, Christianto GAM, et al. Tempeh consumption and cognitive improvement in mild cognitive impairment. Dement Geriatr Cogn Disord. 2020;49(5):497-502. https://doi.org/10.1159/000510563
https://doi.org/10.1159/000510563... .

The essential studies on BDNF roles in AD (Table 1)⁶6 Turana Y, Ranakusuma TAS, Purba JS, Amir N, Ahmad SA, Machfoed MH, et al. Enhancing diagnostic accuracy of aMCI in the elderly: combination of olfactory test, pupillary response test, BDNF plasma level, and APOE genotype. Int J Alzheimers Dis. 2014;2014:912586. https://doi.org/10.1155/2014/912586
https://doi.org/10.1155/2014/912586... ,¹¹⁵115 Angelucci F, Spalletta G, di Iulio F, Ciaramella A, Salani F, Colantoni L, et al. Alzheimer’s disease (AD) and mild cognitive impairment (MCI) patients are characterized by increased BDNF serum levels. Curr Alzheimer Res. 2010;7(1):15-20. https://doi.org/10.2174/156720510790274473
https://doi.org/10.2174/1567205107902744... ,¹¹⁶116 Forlenza OV, Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonça VA, et al. Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment. World J Biol Psychiatry. 2010;11(6):774-80. https://doi.org/10.3109/15622971003797241
https://doi.org/10.3109/1562297100379724... ,¹²⁵125 Yasutake C, Kuroda K, Yanagawa T, Okamura T, Yoneda H. Serum BDNF, TNF-alpha and IL-1beta levels in dementia patients: comparison between Alzheimer’s disease and vascular dementia. Eur Arch Psychiatry Clin Neurosci. 2006;256(7):402-6. https://doi.org/10.1007/s00406-006-0652-8
https://doi.org/10.1007/s00406-006-0652-... –¹³⁹139 Perkovic MN, Borovecki F, Filipcic I, Vuic B, Milos T, Erjavec GN, et al. Relationship between brain-derived neurotrophic factor and cognitive decline in patients with mild cognitive impairment and dementia. Biomolecules. 2023;13(3):570. https://doi.org/10.3390/biom13030570
https://doi.org/10.3390/biom13030570... and the potential therapeutic roles of antioxidants against AD which were registered in the ClinicalTrials.gov database in phase 3 (Table 2)¹⁴⁰140 Zhu CW, Grossman H, Neugroschl J, Parker S, Burden A, Luo X, et al. A randomized, double-blind, placebo-controlled trial of resveratrol with glucose and malate (RGM) to slow the progression of Alzheimer’s disease: a pilot study. Alzheimers Dement (NY). 2018;4:609-16. https://doi.org/10.1016/j.trci.2018.09.009
https://doi.org/10.1016/j.trci.2018.09.0... –¹⁴⁴144 Dysken MW, Sano M, Asthana S, Vertrees JE, Pallaki M, Llorente M, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311(1):33-44. https://doi.org/10.1001/jama.2013.282834
https://doi.org/10.1001/jama.2013.282834... are resumed in the table below. There have been limited validated clinical trials regarding the use of antioxidants against AD that were registered from phase 3 up to now. This study did not include phase 1 and phase 2 clinical trials.

In conclusion, OS is an inescapable consequence of aging, along with other AD hallmarks, forming a complex neuropathology cascade of AD. OS affects brain and blood BDNF levels that follow AD progression, and the antioxidant therapy approach may slow its progression. The use of circulating BDNF levels can be a potential molecular biomarker for the diagnosis of AD and monitoring of its progression upon the given prevention and therapy. Further research must be done to define the diagnostic value of BDNF as an AD biomarker for its application in clinical practice.

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