Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction
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Mitochondrial dysfunction is one of the major intracellular lesions of Alzheimer's disease (AD). However, the causative factors involved in the mitochondrial dysfunction in human AD are not well understood. Here we report that nonglycosylated full-length and C-terminal truncated amyloid precursor protein (APP) accumulates exclusively in the protein import channels of mitochondria of human AD brains but not in age-matched controls. Furthermore, in AD brains, mitochondrially associated APP formed stable approximately 480 kDa complexes with the translocase of the outer mitochondrial membrane 40 (TOM40) import channel and a super complex of approximately 620 kDa with both mitochondrial TOM40 and the translocase of the inner mitochondrial membrane 23 (TIM23) import channel TIM23 in an "N(in mitochondria)-C(out cytoplasm)" orientation. Accumulation of APP across mitochondrial import channels, which varied with the severity of AD, inhibited the entry of nuclear-encoded cytochrome c oxidase subunits IV and Vb proteins, which was associated with decreased cytochrome c oxidase activity and increased levels of H2O2. Regional distribution of mitochondrial APP showed higher levels in AD-vulnerable brain regions, such as the frontal cortex, hippocampus, and amygdala. Mitochondrial accumulation of APP was also observed in the cholinergic, dopaminergic, GABAergic, and glutamatergic neuronal types in the category III AD brains. The levels of translocationally arrested mitochondrial APP directly correlated with mitochondrial dysfunction. Moreover, apolipoprotein genotype analysis revealed that AD subjects with the E3/E4 alleles had the highest content of mitochondrial APP. Collectively, these results suggest that abnormal accumulation of APP across mitochondrial import channels, causing mitochondrial dysfunction, is a hallmark of human AD pathology.
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APP and Aβ, as well as the entire γ-secretase complex, physically associate with mitochondria and can effect changes in mitochondrial function.
“accumulating data certainly do suggest APP and Aβ, as well as the entire γ-secretase complex, physically associate with mitochondria and can effect changes in mitochondrial function [58-67].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [63]
APP blocks mitochondrial import machinery and impairs mitochondrial function in AD brain by forming a complex with translocases of the inner and outer mitochondrial membranes.
“APP blocked mitochondrial import machinery and impaired mitochondrial function in AD brain by forming a complex with translocases of the inner and outer mitochondrial membranes.204”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [204]
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- Authors
- Devi, L., Prabhu, B. M., Galati, D. F., Avadhani, N. G., & Anandatheerthavarada, H. K.
- Affiliations
- University of Pennsylvania (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-08-30
- Volume
- 26
- Issue
- 35
- Pages
- 9057-9068
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6675337
- OpenAlex
- W2076241970
- Cited by
- 792
- References
- 62
- Citations by year
- 2026: 21 · 2025: 21 · 2024: 36 · 2023: 47 · 2022: 53 · 2021: 60 · 2020: 50 · 2019: 37 · 2018: 44 · 2017: 39 · 2016: 36 · 2015: 35 · 2014: 34 · 2013: 40 · 2012: 50
- FWCI
- 19.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG021920, AG 021920)
- National Institute of General Medical Sciences (GM-49683, R01GM049683)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid precursor protein, Alzheimer's disease, mitochondrial dysfunction, Tom40, Tim23, cytochrome c oxidase, hydrogen peroxide, neuronal cell types
- MeSH terms
- Alzheimer Disease, Apolipoproteins E, Biological Transport, Brain, Cadaver, Electron Transport Complex IV, Glycosylation, Humans, Hydrogen Peroxide, Mitochondria, Neurons, Tissue Distribution, Case-Control Studies, Amyloid beta-Protein Precursor, Mitochondrial Proteins, Mitochondrial Membrane Transport Proteins, Mitochondrial Membranes, Apolipoprotein E3, Apolipoprotein E4
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