Review articleAlzheimer’s disease and its treatment by different approaches: A review
Graphical abstract
Introduction
Alzheimer’s disease (AD) is declared as “global public health priority” by WHO, because there is no permanent remedy for AD. So far, there are only well-stated concepts and hypotheses about the cause and drug targets of AD. Based on this concept, medications reduce disease pathology progression [1]. AD is the primary cause of dementia in people above the age of 60. Around 50–75% of people with dementia have Alzheimer’s. As per the statistical data collected worldwide, females are more prone to AD than males, and the risk increases even more with age [2]. People with cardiovascular diseases, hypertension, and diabetes are also at higher risk of having AD later. This probably is the leading cause of increased AD cases in developing countries, owing to people’s lifestyle [3]. Patients with clinical symptoms similar to Alzheimer’s but not showing any pathophysiology related to the disease, can be the individuals who are concerned about apparent loss of memory even when there is no substantiation for impairment. This condition is known as ‘worried well’, the effects of alcohol and drugs, and the people with affective illnesses show such symptoms [4]. Other neurodegenerative disorders with AD like symptoms include frontotemporal dementia and lewy body dementia; inflammatory, metabolic and infectious condition; vascular cognitive impairment; and a series of causes that include obstructive sleep apnoea and transient epileptic amnesia [5].
The presence of Aβ40 aggregates and tau protein fibrils makes up the primary pathological condition of AD. However, the company of any one of them can be due to any non-AD and age related dementia [6]. Their link to any neurodegenerative disorder is not clear. The pathological changes occur long before the actual appearance of the symptoms. Various medical approaches that target these pathological processes have proved unsuccessful in preclinical or clinical trials, mainly because of the low bioavailability, blood-brain barrier penetration, imperfect cell, and low half-life of the drug in present treatments. Therefore, the requirement to have new disease-modifying therapies to avoid the development or lower the pace of these enervating disorders’ is essential.
The convergence of stem cell therapy and nanoparticles holds great promise for studying, diagnosing, and treating neurodegenerative disorders [7]. A rising amount of pre-clinical studies have recommended that transfer of neural stem cells (NSCs) can pose a potential new treatment for neurodegenerative disorders. Though the early anticipation concerning this therapy concentrated on employing NSCs to restore degenerating neurons, the latest reports have associated NSC regulated variations in neurotrophins as an active therapeutic effectiveness [8].
The nanoparticles (NPs) regulated drug delivery techniques enhance bioavailability and drug solubility, hence rendering them greater options [5,9]. Additionally, NPs regulated strategies mediate multiple drugs loading and targeted drug delivery, hence enhancing drug effectiveness. Though, particular NPs can produce grave toxicity deteriorating cellular and tissue organization [10,11]. Thus, NP material should be selected carefully. Also, neurodegenerative disorder occurs due to the misfolding of the protein [12,13]. Nanoparticles are suitable candidates for protein refolding by the second route due to their large surface area and minimum diffusional limitation which facilitate better interactions with charged residues on the surface of the denatured protein [[14], [15], [16], [17]]. In the present review, we discussed the causes of the AD and their treatment by different approaches.
Section snippets
Causes of Alzheimer’s disease
A rational chronological order of the occurrences in AD, along with an acceptable and efficient therapy, is lacking. Interaction of oligomers of Aβ protein with glial cells and neurons results in various pathological and physiological anomalies, comprises mitochondrial dysfunction, stimulation of pro-inflammatory cascades, increased tau phosphorylation and oxidative stress, de-regulation of calcium metabolism, enhanced glycogen synthase kinase (GSK)-3β activity, stimulation of cell death and
Alzheimer’s diseases treatment
Combination therapy is required for the successful treatment of AD, since multiple factors influence the progression of the disease. Multi-targeted drugs can be looked forward to for dealing with multiple symptoms and causes of the disorder. BACE1 has been so far the primary therapeutic target for AD therapies, against Aβ accumulation. However, all the potential drugs developed have not been successful beyond phase II/III trials. The challenges faced still involve low bioavailability, increased
Conclusion and future prospects
While our knowledge of AD has considerably grown over the past years, it still continues to be anything but complete. Most of the unsuccessful phase 3 trials employing monoclonal antibodies targeting Aβ have driven scepticism about the hypothesis. It is noticeable, that patient selection and target engagement complicated a lot of analysis, and a part of patients employed for the trials did not have evidence for AD pathology. However, during most analysis patients with later stage AD were
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References (252)
- et al.
Nanoparticle-mediated approaches for Alzheimer’s disease pathogenesis, diagnosis, and therapeutics
J. Contr. Release
(2019) - et al.
Nanoparticle technology and stem cell therapy team up against neurodegenerative disorders
Adv. Drug Deliv. Rev.
(2019) - et al.
Neural stem cell therapy for neurodegenerative disorders: the role of neurotrophic support
Neurochem. Int.
(2017) - et al.
Phytochemical delivery through nanocarriers: a review
Colloids Surf. B Biointerfaces
(2021) - et al.
Alpha amylase assisted synthesis of TiO2 nanoparticles: structural characterization and application as antibacterial agents
J. Hazard Mater.
(2015) - et al.
Refolding of thermally denatured cholesterol oxidases by magnetic nanoparticles
Int. J. Biol. Macromol.
(2019) - et al.
Glutamate-responsive translation of dendritic GSK3β mRNA triggers a cycle for amplification of reactivated preexisting GSK3β that is indispensable for tau hyperphosphorylation
Neurochem. Int.
(2020) - et al.
New deferiprone derivatives as multi-functional cholinesterase inhibitors: design, synthesis and in vitro evaluation
Eur. J. Med. Chem.
(2020) - et al.
Alzheimer’s disease: an overview of amyloid beta dependent pathogenesis and its therapeutic implications along with in silico approaches emphasizing the role of natural products
J. Neurol. Sci.
(2016) - et al.
Vitamin B5 (d-pantothenic acid) localizes in myelinated structures of the rat brain: potential role for cerebral vitamin B5 stores in local myelin homeostasis
Biochem. Biophys. Res. Commun.
(2020)
Cerebral deficiency of vitamin B5 (D-pantothenic acid; pantothenate) as a potentially-reversible cause of neurodegeneration and dementia in sporadic Alzheimer’s disease
Biochem. Biophys. Res. Commun.
The mitochondrial hypothesis: dysfunction, bioenergetic defects, and the metabolic link to Alzheimer’s disease
Int. Rev. Neurobiol.
IGF-1 receptor differentially regulates spontaneous and evoked transmission via mitochondria at hippocampal synapses
Neuron
Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease
Lancet Neurol.
Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice
Neurobiol. Aging
Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer’s disease neurons
Biochim. Biophys. Acta (BBA) - Mol. Basis Dis.
Accumulation of C-terminal fragments of transactive response DNA-binding protein 43 leads to synaptic loss and cognitive deficits in human TDP-43 transgenic mice
Neurobiol. Aging
Quadruple abnormal protein aggregates in brainstem pathology and exogenous metal-rich magnetic nanoparticles (and engineered Ti-rich nanorods). The substantia nigrae is a very early target in young urbanites and the gastrointestinal tract a key brainstem portal
Environ. Res.
TDP-43 interaction with the intracellular domain of amyloid precursor protein induces p53-associated apoptosis
Neurosci. Lett.
Changes in subunit composition of NMDA receptors in animal models of schizophrenia by repeated administration of methamphetamine
Prog. Neuro Psychopharmacol. Biol. Psychiatr.
Regulation of Pleiotrophin and Fyn in the striatum of rats undergoing L-DOPA-induced dyskinesia
Neurosci. Lett.
Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models
Cell
Targeting Fyn kinase in Alzheimer,s disease
Biol. Psychiatr.
Reactive astrocytes in Alzheimer’s disease: a double-edged sword
Neurosci. Res.
Statins promote the degradation of extracellular amyloid β-peptide by microglia via stimulation of exosome-associated insulin-degrading enzyme (IDE) secretion
J. Biol. Chem.
Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer’s disease
Neurobiol. Aging
Exosomes in Alzheimer’s disease
Neurochem. Int.
Calcium signaling in Alzheimer’s disease & therapies
Biochim. Biophys. Acta Mol. Cell Res.
A hallmark of phospholamban functional divergence is located in the N-terminal phosphorylation domain
Comput. Struct. Biotechnol. J.
Capacitive calcium entry is directly attenuated by mutant presenilin-1, independent of the expression of the amyloid precursor protein
J. Biol. Chem.
Changes in healthcare use by Mexican-American medicare beneficiaries before and after a diagnosis of dementia
J. Gerontol.: Series A
Estrogen-dependent hippocampal wiring as a risk factor for age-related dementia in women
Prog. Neurobiol.
The interrelationship between insulin-like growth factor 1, apolipoprotein E ε4, lifestyle factors, and the aging body and brain
The Journal of Prevention of Alzheimer’s Disease
The effects of alpha-linolenic acid on the secretory activity of astrocytes and β amyloid-associated neurodegeneration in differentiated SH-SY5Y cells: alpha-linolenic acid protects the SH-SY5Y cells against β amyloid toxicity
Oxidative Medicine and Cellular Longevity
Magnetite/Ceria nanoparticle assemblies for extracorporeal cleansing of amyloid-β in Alzheimer’s disease
Adv. Mater.
Antibacterial effect of green synthesized TiO2 nanoparticles
Adv. Sci. Lett.
Protein misfolding and degenerative diseases
Nature Education
Protein misfolding diseases
Annu. Rev. Biochem.
Aptamer-modified gold nanoparticles for colorimetric determination of platelet-derived growth factors and their receptors
Anal. Chem.
Simultaneous immobilization and refolding of heat treated enzymes on TiO2 nanoparticles
Adv. Sci. Eng. Med.
Biosynthesis, characterization and application of TiO2 nanoparticles in biocatalysis and protein folding
J. Protein Proteonomics
Neuronal calcium imaging, excitability, and plasticity changes in the Aldh2-/- mouse model of sporadic Alzheimer’s disease
J. Alzheim. Dis.
GSK3-ARC/Arg3.1 and GSK3-Wnt signaling axes trigger amyloid-β accumulation and neuroinflammation in middle-aged Shugoshin 1 mice
Aging Cell
Evaluation of urinary 8-hydroxy-2-deoxyguanosine level in experimental Alzheimer’s disease: impact of carvacrol nanoparticles
Mol. Biol. Rep.
Isolation and characterization of antibody fragments selective for human FTD brain derived TDP-43 variants
BMC Neurosci.
Biosynthesis and signalling functions of central and peripheral nervous system neurosteroids in health and disease
Essays Biochem.
Antifungal drug miconazole ameliorated memory deficits in a mouse model of LPS-induced memory loss through targeting iNOS
Cell Death Dis.
Taking advantage of the selectivity of histone deacetylases and phosphodiesterase inhibitors to design better therapeutic strategies to treat Alzheimer’s disease
Front. Aging Neurosci.
Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease
Brain
Molecular docking of C-Jun-N-Terminal Kinase (Jnk) with amino-pyrimidine derivatives
Bioinformation
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