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

• Published in: Molecular neurodegeneration Vol. 13; no. 1; p. 2
• Main Authors: Kim, Dong Kyu, Park, Joonho, Han, Dohyun, Yang, Jinhee, Kim, Ahbin, Woo, Jongmin, Kim, Youngsoo, Mook-Jung, Inhee
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 16-01-2018; BioMed Central; BMC
• Subjects: 10-plex tandem mass tag; Alzheimer's disease; Amyloid beta-protein; Analysis; Animal disease model; Development and progression; Genetic aspects; Physiological aspects; Proteomics; Quantitative proteomics; Tau; South Korea; 10-plex tandem mass tag; Animal disease model; Aβ; Tau; Quantitative proteomics; Alzheimer’s disease
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-017-0234-4

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.
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 (ADLP
) mice. The ADLP
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 ADLP
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.
The ADLP
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 ADLP
mice. Bioinformatics analysis of DEPs revealed that ADLP
mice experienced age-dependent active immune responses and synaptic dysfunctions.
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 ADLP
model mice to investigate how both Aβ and tau pathologies regulate the hippocampal proteome. Because the ADLP
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.