title: Decreased proteolytic activity of the mitochondrial amyloid-β degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria.
abstract: Accumulation of amyloid-β peptide (Aβ), the neurotoxic peptide implicated in the pathogenesis of Alzheimer's disease (AD), has been shown in brain mitochondria of AD patients and of AD transgenic mouse models. The presence of Aβ in mitochondria leads to free radical generation and neuronal stress. Recently, we identified the presequence protease, PreP, localized in the mitochondrial matrix in mammalian mitochondria as the novel mitochondrial Aβ-degrading enzyme. In the present study, we examined PreP activity in the mitochondrial matrix of the human brain's temporal lobe, an area of the brain highly susceptible to Aβ accumulation and reactive oxygen species (ROS) production. We found significantly lower hPreP activity in AD brains compared with non-AD age-matched controls. By contrast, in the cerebellum, a brain region typically spared from Aβ accumulation, there was no significant difference in hPreP activity when comparing AD samples to non-AD controls. We also found significantly reduced PreP activity in the mitochondrial matrix of AD transgenic mouse brains (Tg mAβPP and Tg mAβPP/ABAD) when compared to non-transgenic aged-matched mice. Furthermore, mitochondrial fractions isolated from AD brains and Tg mAβPP mice had higher levels of 4-hydroxynonenal, an oxidative product, as compared with those from non-AD and nonTg mice. Accordingly, activity of cytochrome c oxidase was significantly reduced in the AD mitochondria. These findings suggest that decreased PreP proteolytic activity, possibly due to enhanced ROS production, contributes to Aβ accumulation in mitochondria leading to the mitochondrial toxicity and neuronal death that is exacerbated in AD. Clearance of mitochondrial Aβ by PreP may thus be of importance in the pathology of AD.
authors.affiliation: Department of Surgery, College of Physicians and Surgeons of Columbia University, New York, NY, USA.
authors.forename: Nyosha
authors.initials: N
authors.lastname: Alikhani
authors.forename: Lan
authors.initials: L
authors.lastname: Guo
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Yan
authors.forename: Heng
authors.initials: H
authors.lastname: Du
authors.forename: Catarina Moreira
authors.initials: CM
authors.lastname: Pinho
authors.forename: John Xi
authors.initials: JX
authors.lastname: Chen
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Glaser
authors.forename: Shirley ShiDu
authors.initials: SS
authors.lastname: Yan
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000447:Aldehydes / Q000378:metabolism; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000473:pathology / Q000648:ultrastructure*; D016022:Case-Control Studies; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D016229:Amyloid beta-Peptides; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C462359:tert-4-hydroxy-2-nonenal; D003576:Electron Transport Complex IV; C514899:PREP protein, human; D012697:Serine Endopeptidases