Age-Dependent Changes in the Sarkosyl-Insoluble Proteome of APP_SWE/PS1_ΔE9 Transgenic Mice Implicate Dysfunctional Mitochondria in the Pathogenesis of Alzheimer’s Disease

Article type: Research Article

Authors: Thygesen, Camilla^{a; b} | Metaxas, Athanasios^a | Larsen, Martin R.^b | Finsen, Bente^{a; *}

Affiliations: [a] Department of Neurobiology, University of Southern Denmark, Institute of Molecular Medicine, Odense, Denmark | [b] Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

Correspondence: [*] Correspondence to: Bente Finsen, Department of Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsløwsvej 25, 2nd floor, DK-5000 Odense C, Denmark. Tel.: +45 6550 3990; E-mail: [email protected].

Abstract: Background:Alzheimer’s disease (AD), the most common cause of dementia, is characterized by the intra- and extracellular aggregation and accumulation of proteins. The major molecular hallmark is the aggregation of amyloid-β (Aβ) and hyperphosphorylated tau proteins into plaques and tangles, respectively. Evidence points to the pre-fibrillary states of protein aggregates harboring the greatest neurotoxicity. Objective:This study was designed to identify and quantify pre-fibrillary protein species enriched by their insolubility in the detergent sarkosyl in the APPSWE/PS1ΔE9 (APP/PS1) transgenic mouse model of AD. Sarkosyl insoluble fractions were isolated from the brains of APP/PS1 and littermate wild type (Wt) mice to identify pre-fibrillary protein species associated with AD. Methods:Pre-fibrillary protein species were isolated from the brains of 3- and 24-month-old APP/PS1 and littermate Wt mice using sarkosyl extraction and subjected to quantitative proteomics analysis by the use of isobaric tags for relative and absolute quantitation (iTRAQ). Results:The sarkosyl-insoluble pre-fibrillary proteome showed differential age- and genotype-induced effects. In addition to Aβ and tau, old APP/PS1 mice showed significant enrichment in proteins in the sarkosyl fraction involved in oxidative phosphorylation and mitochondrial function. Conclusion:The results of this study implicate dysfunctional mitochondria as playing a key role of Aβ- and potentially tau-induced pathological events in the APP/PS1 transgenic mouse model of AD.

Keywords: Alzheimer’s disease, amyloid-β, APP_SWE/PS1_ΔE9, iTRAQ, mass spectrometry, oxidative stress, proteomics, tau

DOI: 10.3233/JAD-180197

Journal: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1247-1259, 2018