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Comparative profiling of hippocampal gene expression in AppNL-G-F knock-in mouse model of Alzheimer's disease.

ABSTRACT: To identify molecular pathological alterations in Alzheimer’s disease (AD) brains, we had previously performed comparative gene expression profiling with human gene array using RNAs prepared from postmortem human brains donated for the Hisayama study. The hippocampi from AD brains showed the most significant alteration in gene expression profile (PMID: 23595620). In the present study, in order to obtain a comprehensive view of gene expression profiles in AD hippocampus, we applied human transcriptome array and deep RNA-sequencing to the same samples and reanalyzed the gene array data, and performed integrative analysis of all 3 methods. We also applied gene array to hippocampus of 6-month-old App[NL-G-F/NL-G-F] knock-in AD model mice, and at last we performed the interspecies comparison. IPA analysis of the top significantly altered genes derived from integrative analysis of all 3 methods in human AD hippocampus revealed that neurotransmission, synaptic transmission and development of neurons are the top significantly decreased functions. In hippocampi of App[NL-G-F/NL-G-F] mice which exhibit significant amyloidosis but not neuronal degeneration, we found that expression of Gfap (astrocyte marker) and Cd68 (microglia marker) genes are significantly upregulated together with genes categorized in the immune response of cells. Comparing the human and mouse data, we found major common genes are related to recruitment of inflammatory cells. Amyloid-beta accumulation is the major hallmark of AD at 6 month-old App[NL-G-F/NL-G-F] mice, therefore our data suggests that amyloid-beta accumulation increases the recruitment of inflammatory cells in early stage of AD brain, prior to neuronal degeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE157161 | GEO | 2021/12/01

REPOSITORIES: GEO

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Project description:Oxidative stress is a major risk factor for Alzheimer’s disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into AppNL-G-F/NL-G-F knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in AppNL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis.

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Comparative profiling of hippocampal gene expression in AppNL-G-F knock-in mouse model of Alzheimer's disease.

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