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Mol Neurodegener. 2018 Jan 16;13(1):2. doi: 10.1186/s13024-017-0234-4.

Molecular and functional signatures in a novel Alzheimer's disease mouse model assessed by quantitative proteomics.

Author information

1
Department of Biomedical Sciences, Seoul National University, College of Medicine, 103 Daehak-ro, Seoul, 110-799, South Korea.
2
Interdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, 1 Gwanak-ro, Seoul, 151-742, South Korea.
3
Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Seoul, 110-744, South Korea.
4
Interdisciplinary Program in Bioengineering, College of Engineering, Seoul National University, 1 Gwanak-ro, Seoul, 151-742, South Korea. biolab@snu.ac.kr.
5
Department of Biomedical Sciences, Seoul National University, College of Medicine, 103 Daehak-ro, Seoul, 110-799, South Korea. inhee@snu.ac.kr.
6
Neuroscience Research Institute, Seoul National University, College of Medicine, Seoul, 110-799, South Korea. inhee@snu.ac.kr.

Abstract

BACKGROUND:

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. To understand the pathological mechanisms underlying AD, developing animal models that completely encompass the main features of AD pathologies is indispensable. Although mouse models that display pathological hallmarks of AD (amyloid plaques, neurofibrillary tangles, or both) have been developed and investigated, a systematic approach for understanding the molecular characteristics of AD mouse models is lacking.

METHODS:

To elucidate the mechanisms underlying the contribution of amyloid beta (Aβ) and tau in AD pathogenesis, we herein generated a novel animal model of AD, namely the AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) mice. The ADLPAPT mice carry three human transgenes, including amyloid precursor protein, presenilin-1, and tau, with six mutations. To characterize the molecular and functional signatures of AD in ADLPAPT mice, we analyzed the hippocampal proteome and performed comparisons with individual-pathology transgenic mice (i.e., amyloid or neurofibrillary tangles) and wild-type mice using quantitative proteomics with 10-plex tandem mass tag.

RESULTS:

The ADLPAPT mice exhibited accelerated neurofibrillary tangle formation in addition to amyloid plaques, neuronal loss in the CA1 area, and memory deficit at an early age. In addition, our proteomic analysis identified nearly 10,000 protein groups, which enabled the identification of hundreds of differentially expressed proteins (DEPs) in ADLPAPT mice. Bioinformatics analysis of DEPs revealed that ADLPAPT mice experienced age-dependent active immune responses and synaptic dysfunctions.

CONCLUSIONS:

Our study is the first to compare and describe the proteomic characteristics in amyloid and neurofibrillary tangle pathologies using isobaric label-based quantitative proteomics. Furthermore, we analyzed the hippocampal proteome of the newly developed ADLPAPT model mice to investigate how both Aβ and tau pathologies regulate the hippocampal proteome. Because the ADLPAPT mouse model recapitulates the main features of AD pathogenesis, the proteomic data derived from its hippocampus has significant utility as a novel resource for the research on the Aβ-tau axis and pathophysiological changes in vivo.

KEYWORDS:

10-plex tandem mass tag; Alzheimer’s disease; Animal disease model; Aβ; Quantitative proteomics; Tau

PMID:
29338754
PMCID:
PMC5771139
DOI:
10.1186/s13024-017-0234-4
[Indexed for MEDLINE]
Free PMC Article

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