Mitochondrial Abnormalities in Alzheimer’s Disease: Possible Targets for Therapeutic Intervention
Introduction
Alzheimer’s disease (AD) is the most prevalent form of dementia. In the United States, it is estimated that one out of every eight persons over the age of 65 suffers from AD, and almost half of those over the age of 85 are affected (Evans et al., 1989; Thies & Bleiler, 2011). It has also been recognized for some time, as Alois Alzheimer’s first reports were presented and published at the start of the twentieth century (Alzheimer, 1907, 1911; Alzheimer et al., 1995). Many academic clinicians and scientists focus on AD, and industry maintains active AD drug development and testing programs.
All this helps create the false impression that we truly understand what AD is, what causes it, and how to effectively treat it. On the contrary, how we even define the disease is somewhat arbitrary, and this really has been the case since the term “Alzheimer’s disease” was first proposed.
By the late nineteenth century, it was recognized that with advancing age, the brain cortex of some animal species develop extracellular protein accumulations called plaques (Blocq & Marinesco, 1892). During the first decade of the twentieth century, this phenomenon was also noted to occur in the brains of elderly humans, and that this histological change was often associated with dementia, a clinical syndrome characterized by declining cognitive function (Fischer, 1907; Redlich, 1898). At this same time, Alois Alzheimer reported the brains of several relatively young, or “presenile,” demented individuals also developed plaque deposits (Alzheimer, 1907, 1911). Alzheimer further described intracellular protein aggregations which he called tangles. Because dementia was relatively common in those reaching old age, affected persons were not felt to have an actual disease, even when plaques and tangles were present (Kraepelin, 1910). Such persons were simply felt to have a senile dementia syndrome that frequently accompanies old age. It was only those with presenile dementia, plaques, and tangles who actually qualified for an AD diagnosis.
Over the next 100 years, much was learned about the structural basis of the plaques and tangles. The major protein in the plaques is folded in an amyloid configuration (Divry, 1927), and is called beta amyloid (Aβ) (Glenner & Wong, 1984). Aβ arises as a degradation product of a larger protein called the amyloid precursor protein (APP) (Kang et al., 1987). The tangles contain aggregated assemblies of a protein called tau, and tau protein in tangles is heavily phosphorylated (Grundke-Iqbal et al., 1986).
During the second half of the twentieth century, the clinical definition underwent significant revision. The distinction between when a demented person with plaques and tangles was young enough to have AD or old enough to have age-associated senile dementia had always been somewhat arbitrary (Swerdlow, 2007a). To minimize the impact of this distinction (Katzman, 1976), the original AD subjects were stated to have presenile dementia of the Alzheimer’s type, while the elderly subjects were said to have senile dementia of the Alzheimer’s type. However, the age boundary between the presenile and senile conditions was still arbitrary, and most reverted to simply calling the clinical syndrome AD, regardless of age.
In the early 1990s, it was shown that mutations in the APP gene, which resides on chromosome 21, cause brain disease in general and can also cause an AD presentation characterized by progressive dementia, plaques, and tangles (Goate et al., 1991; Levy et al., 1990). This discovery gave rise to a hypothesis, the amyloid cascade hypothesis, that posited AD was itself induced by the presence of Aβ-containing amyloid plaques (Hardy & Allsop, 1991).
It was subsequently discovered that mutations in two other genes, the presenilin 1 (PS1) and presenilin 2 (PS2) genes, caused an AD presentation and that the presenilin proteins contributed to APP processing (Kimberly et al., 2000; Levy-Lahad et al., 1995; Sherrington et al., 1995; Wolfe et al., 1999). Aβ was found to be toxic under cell culture conditions (Yankner et al., 1989), and although belief that plaques drove AD neurodysfunction and neurodegeneration gradually fell out of favor, modified versions of the amyloid cascade hypothesis in which different preplaque Aβ configurations were deemed the critical toxic moiety increasingly came to dominate the field (Hardy & Selkoe, 2002; Walsh & Selkoe, 2007). Consistent with this view, transgenic mouse models that developed cortical plaques were created and became the mainstay of preclinical AD research (Hsiao et al., 1996).
Along the way, clinically based AD concepts began to clash with the amyloid cascade hypothesis. The most important discrepancy arose from the fact that plaques are often observed in the brains of the nondemented elderly, a finding not entirely consistent with the idea that Aβ is the primary disease mediator (Swerdlow, 2011a). Recently, this has been administratively addressed by expanding the definition of AD to include anyone with brain plaques, regardless of clinical status. Those with plaques and dementia are now said to have AD, while those with plaques and no clinical signs can be diagnosed with “preclinical AD” (Sperling et al., 2011).
So, despite the fact that many people are diagnosed with it, many investigators study it, and much has been written about it, what we now call AD remains a somewhat arbitrary construct whose definition is subject to change. In essence, the same controversies that were identified over 100 years ago remain. We still do not know whether AD is a single homogeneous entity or a collection of clinically and histologically overlapping conditions. The relationship between brain aging and AD is unclear. Whether Aβ truly induces a disease-driving cascade in all or even some patients remains unproven. To date, a number of therapeutic interventions that benefit AD transgenic mice have been shown not to benefit affected patients, which raises the question of how well these mice model human AD (Holmes et al., 2008; Swerdlow, in press, Swerdlow, 2007a). With this in mind, this chapter will now address the role of mitochondria in AD and the possibility that mitochondria might offer a potential AD therapeutic target.
Section snippets
Mitochondrial Function in AD
AD is usually thought of as a disease of the brain. Biochemical changes, though, are certainly not brain-limited (Swerdlow, 2012). Systemic mitochondrial changes between the mitochondria of AD and age-matched control subjects have been observed.
Mitochondria as a Therapeutic Target in AD
Accumulating data suggest mitochondrial function, if not changes in cell bioenergetics or the pathways that regulate cell bioenergetics, is perturbed early in the course of AD. In this respect, it is possible that at the commencement of AD itself mitochondria are altered by a more upstream process. If so, then treating mitochondrial abnormalities may benefit affected patients to some degree. It may also be the case that mitochondrial or bioenergetic dysfunction may actually constitute the
Conclusion
Many key questions about AD remain unresolved. There is no uniform agreement over whether AD is a homogeneous or a heterogeneous entity, how it relates to brain aging, or even what causes most of the cases. It is clear from a population perspective that mitochondria and mitochondria-related phenomena differ between those who do and do not have this disease. The importance of these mitochondrial and bioenergetic differences to AD, however it is defined, has been variably considered to be
Acknowledgments
The authors receive support from the University of Kansas Alzheimer’s Center (NIA P30AG035982), the Frank and Evangeline Thompson Alzheimer’s Disease Therapeutic Development Fund, and the Portugal Institute of Science and Technology.
Conflict of Interest Statement: The authors have no conflicts of interest to declare.
References (298)
- et al.
Activation of caspase-6 in aging and mild cognitive impairment
American Journal of Pathology
(2007) - et al.
Brain mitochondria as a primary target in the development of treatment strategies for Alzheimer disease
International Journal of Biochemistry & Cell Biology
(2009) - et al.
Mitochondrial decay in aging
Biochimica et Biophysica Acta
(1995) - et al.
Caspase-3 cleaved spectrin colocalizes with neurofilament-immunoreactive neurons in Alzheimer’s disease
Neuroscience
(2006) - et al.
Mitochondria, oxidants, and aging
Cell
(2005) Biochemical effects of SIRT1 activators
Biochimica et Biophysica Acta
(2010)- et al.
Alzheimer’s disease: New approaches to drug discovery
Current Opinion in Chemical Biology
(2009) - et al.
Oxidative stress in Alzheimer disease: A possibility for prevention
Neuropharmacology
(2010) - et al.
Microtubule-stabilizing agent prevents protein accumulation-induced loss of synaptic markers
European Journal of Pharmacology
(2007) - et al.
Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer’s disease
Neurobiology of Disease
(2006)
Elevated protein-bound levels of the lipid peroxidation product, 4-hydroxy-2-nonenal, in brain from persons with mild cognitive impairment
Neuroscience Letters
Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer’s disease
Brain Research
Oxidative stress as a mediator of apoptosis
Immunology Today
Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer’s disease neurons
Biochimica et Biophysica Acta
Methylene blue improves brain oxidative metabolism and memory retention in rats
Pharmacology, Biochemistry, and Behavior
Mitochondrial control of autophagic lysosomal pathway in Alzheimer’s disease
Experimental Neurology
Cytochrome c oxidase is decreased in Alzheimer’s disease platelets
Neurobiology of Aging
Microtubule reduction in Alzheimer’s disease and aging is independent of tau filament formation
American Journal of Pathology
Proteomic identification of oxidatively modified proteins in Alzheimer’s disease brain. Part I: Creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1
Free Radical Biology & Medicine
Mitochondria: dynamic organelles in disease, aging, and development
Cell
Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer disease
Brain Research. Molecular Brain Research
The frequency of point mutations in mitochondrial DNA is elevated in the Alzheimer’s brain
Biochemical and Biophysical Research Communications
Mitochondrial fusion protects against neurodegeneration in the cerebellum
Cell
Quantitative assessment of DNA fragmentation and beta-amyloid deposition in insular cortex and midfrontal gyrus from patients with Alzheimer’s disease
Life Science
Marked changes in mitochondrial DNA deletion levels in Alzheimer brains
Genomics
Caspase-mediated degeneration in Alzheimer’s disease
American Journal of Pathology
Oxidative metabolism in cultured fibroblasts derived from sporadic Alzheimer’s disease (AD) patients
Neuroscience Letters
Impaired axonal transport of cortical neurons in Alzheimer’s disease is associated with neuropathological changes
Brain Research
Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer’s disease
Laboratory Investigation
A femtomolar acting octapeptide interacts with tubulin and protects astrocytes against zinc intoxication
Journal of Biological Chemistry
Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer’s disease: a randomised, double-blind, placebo-controlled study
Lancet
The mitochondrial impairment, oxidative stress and neurodegeneration connection: Reality or just an attractive hypothesis?
Trends in Neurosciences
Cause and consequence: Mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases
Biochimica et Biophysica Acta
Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein
Biochemical and Biophysical Research Communications
Efficacy of minocycline in patients with amyotrophic lateral sclerosis: A phase III randomised trial
Lancet Neurology
The expression of several mitochondrial and nuclear genes encoding the subunits of electron transport chain enzyme complexes, cytochrome c oxidase, and NADH dehydrogenase, in different brain regions in Alzheimer’s disease
Neurochemical Research
Redox proteomics analysis of brains from subjects with amnestic mild cognitive impairment compared to brains from subjects with preclinical Alzheimer’s disease: Insights into memory loss in MCI
Journal of Alzheimer’s Disease
Uber eine eigenartige Erkrankung der Hirnrinde
Allgemeine Zeitschrift fur Psychiatrie Psych-Gerichtl Med
Uber eigenartige Krankheitsfalle des spateren Alters
Zeitschrift für die gesamte Neurologie und Psychiatrie
An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”
Clinical Anatomy
DNA damage and apoptosis in Alzheimer’s disease: Colocalization with c-Jun immunoreactivity, relationship to brain area, and effect of postmortem delay
Journal of Neuroscience
Neuronal protection by sirtuins in Alzheimer’s disease
Journal of Neurochemistry
Oxidative stress in the progression of Alzheimer disease in the frontal cortex
Journal of Neuropathology and Experimental Neurology
Mitochondrial fusion/fission, transport and autophagy in Parkinson’s disease: when mitochondria get nasty
Parkinsons’s Disease
Protective role of methylene blue in Alzheimer’s disease via mitochondria and cytochrome c oxidase
Journal of Alzheimer’s Disease
Methylene blue delays cellular senescence and enhances key mitochondrial biochemical pathways
FASEB Journal
Alzheimer disease: Caspases first
Nature Reviews. Neurology
Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1
FASEB Journal
Mitochondria as a target for neurotoxins and neuroprotective agents
Annals of the New York Academy of Sciences
Peripheral oxidative damage in mild cognitive impairment and mild Alzheimer’s disease
Journal of Alzheimer’s Disease
Cited by (69)
Apolipoprotein E4 heterologous expression, purification under non-denaturing conditions, and effects on neuronal clonal cell lines
2023, Protein Expression and PurificationEvidence for a Geroscience Approach to Late Life Depression: Bioenergetics and the Frail-Depressed
2022, American Journal of Geriatric PsychiatryFormulation and optimization of bioinspired rosemary extract loaded PEGylated nanoliposomes for potential treatment of Alzheimer's disease using design of experiments
2021, Journal of Drug Delivery Science and TechnologyCitation Excerpt :As a primary toxicological event, oxidative stress is characterized by reactive oxygen species (ROS) which at higher concentrations are engendering the nucleic acid, protein and lipid oxidation [4]. Many research studies have suggested that the basic mechanisms which induce oxidative stress are mitochondrial dysfunction [5], metal accumulation [6], hyperphosphorilated tau [3], Aβ accumulation [2] and inflammation [7]. As a crucial upstream factor in the pathogenesis of the disease, oxidative stress accompanies pathological changes in AD and therefore its products represent potential biomarkers in blood for diagnosis.
Rosmarinic acid and mitochondria
2021, Mitochondrial Physiology and Vegetal Molecules: Therapeutic Potential of Natural Compounds on Mitochondrial HealthDeclining Skeletal Muscle Mitochondrial Function Associated With Increased Risk of Depression in Later Life
2019, American Journal of Geriatric PsychiatryAcetylation as a major determinant to microtubule-dependent autophagy: Relevance to Alzheimer's and Parkinson disease pathology
2019, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Remarkably, both diseases share a common neuropathological feature such as the deposition of specific misfolded proteins [2]. In PD there is the presence of intracytoplasmic inclusions (Lewy bodies, LBs) which comprise a dense core of different proteins, being the main one ASYN [3] whereas in AD there is the presence of amyloid plaques, composed of amyloid-β (Aβ), a cleavage peptide derived from amyloid precursor protein (APP), and neurofibrillary tangles (NFTs), primarily composed of hyperphosphorylated Tau [4]. Notwithstanding, Tau deposition is found in other neurodegenerative brain diseases.
- 1
These authors contributed equally to this work.