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

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 (A β) 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 APP SWE /PS1 ΔE9 (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 A β 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 A β- and potentially tau-induced pathological events in the APP/PS1 transgenic mouse model of AD.