title: Quantitative proteomic analysis of the hippocampus in the 5XFAD mouse model at early stages of Alzheimer's disease pathology.
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.
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea.
authors.forename: Ingie
authors.initials: I
authors.lastname: Hong
authors.forename: Taewook
authors.initials: T
authors.lastname: Kang
authors.forename: Yongcheol
authors.initials: Y
authors.lastname: Yoo
authors.forename: Royun
authors.initials: R
authors.lastname: Park
authors.forename: Junuk
authors.initials: J
authors.lastname: Lee
authors.forename: Sukwon
authors.initials: S
authors.lastname: Lee
authors.forename: Jeongyeon
authors.initials: J
authors.lastname: Kim
authors.forename: Boemjong
authors.initials: B
authors.lastname: Song
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Minho
authors.initials: M
authors.lastname: Moon
authors.forename: Ki Na
authors.initials: KN
authors.lastname: Yun
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Park
authors.forename: Sukwoo
authors.initials: S
authors.lastname: Choi
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D053719:Tandem Mass Spectrometry; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D008562:Membrane Glycoproteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D020543:Proteome; D014157:Transcription Factors; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases