Quantitative proteomic analysis of the hippocampus in the 5XFAD mouse model at early stages of Alzheimer's disease pathology

Ingie Hong, Taewook Kang, Yong Cheol Yoo, Royun Park, Junuk Lee, Sukwon Lee, Jeongyeon Kim, Boemjong Song, Se Young Kim, Minho Moon, Ki Na Yun, Jin Young Kim, Inhee Mook-Jung, Young Mok Park, Sukwoo Choi

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer's disease (AD) is characterized by progressive memory loss accompanied by synaptic and neuronal degeneration. Although research has shown that substantial neurodegeneration occurs even during the early stages of AD, the detailed mechanisms of AD pathogenesis are largely unknown because of difficulties in diagnosis and limitations of the analytical methods. The 5XFAD mouse model harbors five early-onset familial AD (FAD) mutations and displays substantial amyloid plaques and neurodegeneration. Here, we use quantitative mass spectrometry to identify proteome-wide changes in the 5XFAD mouse hippocampus during the early stages of AD pathology. A subset of the results was validated with immunoblotting. We found that the 5XFAD mice display higher expression of ApoE, ApoJ (clusterin), and nicastrin, three important proteins in AD that are known to participate in amyloid-β processing and clearance, as well as the neurological damage/glial marker protein GFAP and other proteins. A large subset of the proteins that were up- or downregulated in 5XFAD brains have been implicated in neurological disorders and cardiovascular disease, suggesting an association between cardiovascular disease and AD. Common upstream regulator analysis of upregulated proteins suggested that the XBP1, NRF2, and p53 transcriptional pathways were activated, as was IGF-1R signaling. Protein interactome analysis revealed an interconnected network of regulated proteins, with two major sub-networks centered on AβPP processing membrane complexes and mitochondrial proteins. Together with a recent study on the transcriptome of 5XFAD mice, our study allows a comprehensive understanding of the molecular events occurring in 5XFAD mice during the early stages of AD pathology.

Original languageEnglish (US)
Pages (from-to)321-334
Number of pages14
JournalJournal of Alzheimer's Disease
Volume36
Issue number2
DOIs
StatePublished - 2013
Externally publishedYes

Keywords

  • Alzheimer's disease
  • amyloid-β
  • memory
  • mild cognitive impairment
  • proteomics
  • PS1
  • transgenic mice

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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