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The Journal of Neuroscience, August 30, 2006, 26(35):9057-9068; doi:10.1523/JNEUROSCI.1469-06.2006

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

Latha Devi, Badanavalu M. Prabhu, Domenico F. Galati, Narayan G. Avadhani, and Hindupur K. Anandatheerthavarada

Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Correspondence should be addressed to Hindupur K. Anandatheerthavarada, Department of Animal Biology, School of Veterinary Medicine, 3800 Spruce Street, University of Pennsylvania, Philadelphia, PA 19104. Email: ann1234{at}vet.upenn.edu

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 "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.

Key words: mitochondria; protein import; translocational arrest; amyloid precursor protein; Alzheimer’s disease; amyloid-

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Received April 5, 2006; revised July 25, 2006; accepted July 28, 2006.

Correspondence should be addressed to Hindupur K. Anandatheerthavarada, Department of Animal Biology, School of Veterinary Medicine, 3800 Spruce Street, University of Pennsylvania, Philadelphia, PA 19104. Email: ann1234{at}vet.upenn.edu

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