Abstract
Alzheimer’s disease (AD) is the most common form of dementia, characterized by accumulation of amyloid β (Aβ) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Aβ pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the AppNL-G-F/NL-G-F and 3xTg-AD-H mouse models. Genes commonly altered in AppNL-G-F/NL-G-F and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the AppNL-G-F/NL-G-F cortex as Aβ amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The AppNL-G-F/NL-G-F cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical Aβ amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia, characterized by accumulation of amyloid β (Aβ) and neurofibrillary tangles
By analysing expression profiles of these subjects using Transcriptome Analysis Console (TAC) and Ingenuity Pathway Analysis (IPA) software, we found that 1372 (781 up, 591 down) genes in the temporal cortex and 236 (33 up, 203 down) genes in the frontal cortex were differentially expressed between AD and non-AD cases (ANOVA: P < 0.05, a lower bi-weight average signal > 6.64, a fold change ≥ 1.2 or ≤−1.2) (Supplementary Tables S3 and S4)
We performed inter-species comparative gene expression profiling using cortical RNA prepared from AD patient brains and two different AD mouse models (AppNL-G-F/ NL-G-F and 3xTg-AD-H)
Summary
Alzheimer’s disease (AD) is the most common form of dementia, characterized by accumulation of amyloid β (Aβ) and neurofibrillary tangles. The AppNL-G-F/NL-G-F cortex had altered expression of genes (Abi[3], Apoe, Bin[2], Cd33, Ctsc, Dock[2], Fcer1g, Frmd[6], Hck, Inpp5D, Ly86, Plcg[2], Trem[2], Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD These results suggest a strong correlation between cortical Aβ amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD. Transgenic mouse models overexpress genetically modified Aβ precursor protein (APP), presenilin (PSEN) and/or the microtubule-associated protein tau (MAPT), to induce accumulation of Aβ or neuronal dysfunction These transgenic mouse models develop AD-like pathologies at different ages and to different extents due to expression levels of AD-related proteins that are dependent on promoters used in transgene constructs, as well as copy number of transgenes and inserted regions[7,8,9]. Cortical areas play an important role in the maintenance of brain integrity; novel imaging technologies show Aβ depositions and morphological alterations in the cortex of AD patients[12,13,14,15,16], raising the question of how Aβ accumulation in the brain cortex is involved in pathophysiological alterations observed in AD
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