Decreased Proteolytic Activity of the Mitochondrial Amyloid-β Degrading Enzyme, PreP Peptidasome, in Alzheimer's Disease Brain Mitochondria

Article type: Research Article

Authors: Alikhani, Nyosha^{a; e; 1} | Guo, Lan^{a; 1} | Yan, Shiqiang^a | Du, Heng^a | Pinho, Catarina Moreira^e | Chen, John Xi^f | Glaser, Elzbieta^e | Yan, Shirley ShiDu^{a; b; c; d; *}

Affiliations: [a] Department of Surgery, College of Physicians and Surgeons of Columbia University, New York, NY, USA | [b] Department of Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, NY, USA | [c] Department of Taub Institute for Research on Alzheimer's disease and the Aging Brain, College of Physicians & Surgeons of Columbia University, New York, NY, USA | [d] Department of Pharmacology and Toxicoogy and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA | [e] Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden | [f] Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Correspondence: [*] Correspondence to: Shirley ShiDu Yan, Department of Pharmacology and Toxicology, Higuchi Bioscience Center School of Pharmacy, University of Kansas, 2099 Constant Avenue, Lawrence, KS 66047, USA. Tel.: +1 785 864 3637; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

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.

Keywords: Mitochondrial amyloid-β, mitochondrial function, oxidative stress, presequence protease (PreP), proteolysis

DOI: 10.3233/JAD-2011-101716

Journal: Journal of Alzheimer's Disease, vol. 27, no. 1, pp. 75-87, 2011