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P2‐012: A genome wide scan for genetic variations with inverse association between Alzheimer's disease and breast cancer
Author(s) -
Veera Manikandan R.,
Anand R.
Publication year - 2015
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2015.06.548
Subject(s) - genome wide association study , single nucleotide polymorphism , breast cancer , genetic association , genetics , biology , cancer , disease , gene , bioinformatics , medicine , genotype
some genetically engineered mouse models (GEMMs) recapitulate either the amyloid or the tau based neuropathology observed in AD but not both features of the human disease. Methods:To better understand the relevance of preclinical models to AD, we generated genome-wide transcriptome profiles by next generation sequencing of frontal cortex from GEMMs with amyloidosis (Tg2576) or tauopathy (Tg4510) at ages spanning the onset of pathology. Results: Significant age-dependent transcriptional changes were observed within each model. Although Tg4510 animals exhibited the greatest number and magnitude of changes, there were also many changes observed across both GEMMs. These results were compared to transcriptional modules correlating with normal aging and/or AD disease onset and progression in human brain tissue samples to determine which aspects of the human disease were present in each model. Whereas each GEMM induced gene modules associated with human aging, only Tg4510 exhibited human ADspecific signatures, suggesting that the Tg4510 mouse model may capture more aspects of biological change associated with AD than amyloidosis models. To extend these results, we generated similar transcriptional profiles from Tg4510 mice administered O-GlcNAcase (OGA) inhibitor, a treatment which reduces tau pathology and neurodegeneration in mouse. Chronic OGA inhibition reversed many transcriptional signatures specific to the progression of Tg4510 pathology and found in human AD brain. Conclusions: These studies highlight the utility of transcriptional profiling in determining relevance of preclinical models.