The online version of this article (https://doi.org/10.1186/s13024-017-0234-4) contains supplementary material, which is available to authorized users.
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 (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.
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.
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.
Additional file 1: Supplementary Methods. (DOCX 31 kb)13024_2017_234_MOESM1_ESM.docx
Additional file 2: Figure S1. Pathological characterization of a novel animal model of Alzheimer’s disease. Figure S2. Activated neuroinflammation in a novel animal model of Alzheimer’s disease. Figure S3. TMT-based protein quantification strategy. Figure S4. The comparative analysis between ADLPAPT and other AD proteome datasets. Figure S5. The quality assessment of MS analysis. Figure S6. The expression levels of exclusive DEPsAPT in other ADLP mice. Figure S7. Longitudinal expression changes of kinases involved in phosphorylation of tau protein. (PPTX 2370 kb)13024_2017_234_MOESM2_ESM.pptx
Additional file 3: Table S1. All identified protein groups. (XLSX 1130 kb)13024_2017_234_MOESM3_ESM.xlsx
Additional file 4: Table S2. All quantified protein groups. (XLSX 4540 kb)13024_2017_234_MOESM4_ESM.xlsx
Additional file 5: Table S3. Significantly regulated proteins from t-test. (XLSX 170 kb)13024_2017_234_MOESM5_ESM.xlsx
Additional file 6: Table S4. DEPs from ANOVA test. (XLSX 391 kb)13024_2017_234_MOESM6_ESM.xlsx
Additional file 7: Table S5. Canonical pathways enriched by IPA analysis. (XLSX 18 kb)13024_2017_234_MOESM7_ESM.xlsx
Additional file 8: Table S6. DEPs in ADLPAPT mice, DEPsAPT. (XLSX 195 kb)13024_2017_234_MOESM8_ESM.xlsx
Additional file 9: Table S7. GO analysis results in ADLPAPT mice. (XLSX 41 kb)13024_2017_234_MOESM9_ESM.xlsx
Additional file 10: Table S8. IPA analysis results in ADLPAPT mice. (XLSX 53 kb)13024_2017_234_MOESM10_ESM.xlsx
Additional file 11: Table S9. Exclusive DEPsAPT. (XLSX 31 kb)13024_2017_234_MOESM11_ESM.xlsx
Additional file 12: Table S10. GO analysis of commonly significant proteins in human and ADLPAPT. (XLSX 13 kb)13024_2017_234_MOESM12_ESM.xlsx
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- Molecular and functional signatures in a novel Alzheimer’s disease mouse model assessed by quantitative proteomics
Dong Kyu Kim
- BioMed Central