Quantitative Proteomic Analysis of the Hippocampus in the 5XFAD Mouse Model at Early Stages of Alzheimer's Disease Pathology

Article type: Research Article

Authors: Hong, Ingie^{a; 1} | Kang, Taewook^{b; c; 1} | Yoo, YongCheol^{c; 1} | Park, Royun^{d; 1} | Lee, Junuk^a | Lee, Sukwon^a | Kim, Jeongyeon^a | Song, Boemjong^a | Kim, Se-Young^c | Moon, Minho^d | Yun, Ki Na^c | Kim, Jin Young^c | Mook-Jung, Inhee^{d; *} | Park, Young Mok^{b; c; *} | Choi, Sukwoo^{a; *}

Affiliations: [a] School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Korea | [b] Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, Daejeon, Korea | [c] Mass Spectrometry Research Center, Korea Basic Science Institute, Ochang, Korea | [d] Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea

Correspondence: [*] Correspondence to: Sukwoo Choi, Ph.D., School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea. E-mail: sukwoo12@snu.ac.kr; Young Mok Park, Ph.D., Mass Spectrometry Research Center, Korea Basic Science Institute, Ochang 363-883, Korea. E-mail: ympark@kbsi.re.kr; Inhee Mook-Jung, Ph.D., Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, 28 Yungun-dong, Jongno-gu, Seoul 110–799, Korea. E-mail: inhee@snu.ac.kr.

Note: [1] These authors contributed equally to this work.

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.

Keywords: Alzheimer's disease, amyloid-β, memory, mild cognitive impairment, PS1, proteomics, transgenic mice

DOI: 10.3233/JAD-130311

Journal: Journal of Alzheimer's Disease, vol. 36, no. 2, pp. 321-334, 2013