Age-Dependent Changes in the Sarkosyl-Insoluble Proteome of APPSWE/PS1ΔE9 Transgenic Mice Implicate Dysfunctional Mitochondria in the Pathogenesis of Alzheimer's Disease

Camilla Thygesen, Athanasios Metaxas, Martin R Larsen, Bente Finsen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
JournalJournal of Alzheimer's disease : JAD
Volume64
Issue number4
Pages (from-to)1247-1259
ISSN1387-2877
DOIs
Publication statusPublished - 1. Jan 2018

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Keywords

  • APPSWE/PS1ΔE9
  • Alzheimer’s disease
  • amyloid-β
  • iTRAQ
  • mass spectrometry
  • oxidative stress
  • proteomics
  • tau

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