Age-Dependent Changes in the Sarkosyl-Insoluble Proteome of APP(SWE)/PS1(Delta E9) Transgenic Mice Implicate Dysfunctional Mitochondria in the Pathogenesis of Alzheimer's Disease

作者：Thygesen Camilla; Metaxas Athanasios; Larsen Martin R; Finsen Bente^*

来源：Journal of Alzheimer's Disease, 2018, 64(4): 1247-1259.

DOI：10.3233/JAD-180197

• Alzheimer's disease
• amyloid-beta
• APP(SWE)/PS1(Delta E9)
• iTRAQ
• mass spectrometry
• oxidative stress
• proteomics
• tau

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-beta (A beta) 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(Delta E9) (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 beta 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 beta- and potentially tau-induced pathological events in the APP/PS1 transgenic mouse model of AD.

• 出版日期2018