Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer’s Disease Brain Is Associated with Mitochondrial Dysfunction

By L. Devi, B. M. Prabhu, D. Galati, N. Avadhani, H. Anandatheerthavarada. Journal of Neuroscience, 2006

782 citations recorded by the source corpus.

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 ∼480 kDa complexes with the translocase of the outer mitochondrial membrane 40 (TOM40) import channel and a super complex of ∼620 kDa with both mitochondrial TOM40 and the translocase of the inner mitochondrial membrane 23 (TIM23) import channel TIM23 in an “Nin mitochondria–Cout 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.

Subfields: Molecular Biology, Pharmacology, Physiology

View Paper: https://www.semanticscholar.org/paper/1e12a0222fe3e5fdeb85592e45172495678d2154

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In Molecular Biology

1. P. Reddy
2. M. Beal
3. R. Swerdlow
4. M. Mańczak
5. J. Burns
6. M. Calkins
7. C. Zhong
8. Zhichun Chen

In Pharmacology

1. M. Beal
2. P. Reddy
3. R. Swerdlow
4. M. Calkins
5. M. Mańczak
6. Shaharyar M. Khan

In Physiology

1. P. Reddy
2. M. Beal
3. R. Swerdlow
4. J. Burns
5. M. Calkins
6. M. Mańczak
7. Shaharyar M. Khan
8. Xiongwei Zhu

Citations in the corpus

• Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. (2013, background): “The definitive evidence has shown that Ab accumulation in mitochondria of AD patients and mouse models occurs before extracellular amyloid deposition and increases with age (Devi et al., 2006; Du et al., 2008; Hirai et al., 2001; Manczak et al., 2006).”
• Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology. (2010, background): “[28] reported that AβPP, due to its chimeric NH2-terminal signal, is targeted to cortical neuronal mitochondria in a Tg mouse model of AD and the accumulation of full-length AβPP in the mitochondrial compartment in a membranearrested form causes mitochondrial dysfunction and impaired energy metaboli”
• The Interplay Between Mitochondrial Dynamics and Mitophagy (2011, background): “Under these conditions, accumulation of dysfunctional mitochondria leads to oxidative stress and impairs cell function (21, 63, 99, 107).”
• Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. (2008, background): “Mitochondrial oxidative stress occurs early in AD progression, before the onset of Aβ pathology [1,2,16,47].”
• Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer's disease. (2011, background): “At 16 DIV, we found that a portion of A11 immunopositive oligomeric Ab colocalized with mitochondria, confirming previous reports (21,27,28,34).”
• The amyloid β-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae (2008, background): “The reported incomplete mitochondrial translocation of APP leaving the A region outside the mitochondrial membrane (24, 25) suggests that A cannot be generated locally in mitochondria.”
• Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future (2023, background): “It has been demonstrated that 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) In addition, endoplasmic reticulum (ER)-mitochondria contact sites provide a platform t”
• Mitochondrial dysfunction - the beginning of the end in Alzheimer's disease? Separate and synergistic modes of tau and amyloid-β toxicity (2011, background): “Crucial to this fi nding was the notion that both Aβ and the full length protein, APP, accumulate within mitochondria in the brains of AD patients [6,19-21].”
• Interrelation of Oxidative Stress and Inflammation in Neurodegenerative Disease: Role of TNF (2015, background): “In particular, mitochondrial damage may be caused by intracellular APP and/or Aβ, since these proteins can directly bind to the protein import machinery of mitochondria thereby impairing import of mitochondrial proteins [50].”
• The Alzheimer's Disease Mitochondrial Cascade Hypothesis: Progress and Perspectives (2013, background): “To this end, 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].”