Mitochondrial Abnormalities in Alzheimer's Disease

By George Perry, K. Hirai, G. Aliev, A. Nunomura, S. Siedlak, Mark A. Smith. Journal of Neuroscience, 2001

1,370 citations recorded by the source corpus.

The finding that oxidative damage, including that to nucleic acids, in Alzheimer's disease is primarily limited to the cytoplasm of susceptible neuronal populations suggests that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress of Alzheimer's disease. In this study, we used in situhybridization to mitochondrial DNA (mtDNA), immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there are mitochondrial abnormalities in Alzheimer's disease and their relationship to oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine. We found that the same neurons showing increased oxidative damage in Alzheimer's disease have a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm and in the case of mtDNA, the vacuoles associated with lipofuscin. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in Alzheimer's disease.

Subfields: Molecular Biology, Pharmacology, Physiology

View Paper: https://www.semanticscholar.org/paper/efa72bdbf7f6f91ea691c291cececa5ab4faea51

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In Molecular Biology

1. P. Reddy
2. M. Duchen
3. A. Abramov
4. M. Beal
5. R. Swerdlow
6. M. Mańczak
7. J. Burns
8. M. Calkins

In Pharmacology

1. P. Reddy
2. M. Beal
3. E. Masliah
4. Yan Zhao
5. Bradley T. Hyman
6. Matthew P. Frosch
7. Baolu Zhao
8. R. Swerdlow

In Physiology

1. P. Reddy
2. M. Beal
3. M. Duchen
4. R. Swerdlow
5. A. Abramov
6. J. Burns
7. M. Calkins
8. Xiongwei Zhu

Citations in the corpus

• Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. (2008, methodology): “Mitochondrial abnormalities have been found both in neurons and astrocytes [47,54,59], suggesting that both neurons and astrocytes may be damaged by free radicals in the AD brain.”
• Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. (2011, background): “AD is also associated with inflammatory responses, synaptic damage and mitochondrial structural and functional abnormalities (3-10).”
• Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease (2012, background): “[69] also found that neurons with elevated mtDNA mutations demonstrated increased nitrotyrosine immunoreactivity and mitochondrial structural damage in AD brain.”
• Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer’s Disease Brain Is Associated with Mitochondrial Dysfunction (2006, result): “In support of others studies (Hirai et al., 2001; Caspersen et al., 2005; Crouch et al., 2005; Manczak et al., 2006), in the present study, we also observed A species in the mitochondria of AD brain (Fig.”
• The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae (2008, background): “It is noteworthy that in AD at an early stage there is already a reduction in the number of mitochondria (14), the brain glucose metabolism is decreased (15), and the activities of both tricarboxylic acid cycle enzymes (16) and cytochrome c oxidase (COX) are reduced (17–20).”
• Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins (2008, background): “Quantitative morphometric analysis of mitochondria shows increased abnormal and damaged mitochondria in AD (9, 10).”
• Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. (2013, background): “COX impairment is also found in the cingulate cortex and other cortical brain regions of AD patients (Hirai et al., 2001).”
• Oxidative Stress and the Pathogenesis of Alzheimer's Disease (2013, background): “These mitochondrial abnormalities were found accompanied by oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine, indicating that the mitochondria were damaged during the progression of AD [72].”
• Molecular pathways to neurodegeneration (2004, background): “Oxidative stress from mitochondrial dysfunction occurs early in AD, and Aβ may directly or indirectly injure mitochondri”
• The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives (2013, background): “In aggregate, AD subject brains and blood cells contain less PCR-amplifiable mtDNA [47, 105, 109-111].”
• Mitochondrial dysfunction - the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid-β toxicity (2011, background): “Furthermore, morphometric analyses revealed that mito chondria display structural abnormalities, as illustrated by the accumulation of mitochondrial DNA and proteins in the cytoplasm and vacuoles; this accelerates mitochondrial degradation and thereby leads to a signifi cant decrease in mitochondria”
• Oxidative Damage Is the Earliest Event in Alzheimer Disease (2001, background): “While we do not know the source of the hydroxyl radicals, mitochondrial dysfunction (41), intraneuronal Ab accumulation (42), and redox-active metals (43) are candidates, and it is tempting to consider that redox active metals bound in close proximity to RNA are involved.”