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

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. Overall design: Six month-old female wild-type and App[NL-G-F/NL-G-F] mice harboring three pathogenic App-knock-in mutations, that promote aggressive amyloidosis by increasing total Aβ production (Swedish mutation KM670/671NL) and increasing the Aβ42 aggregation (Arctic mutation E693G) and increasing the Aβ42/Aβ40 ratio (Iberian mutation I716F) under the control of the endogenous APP promoter were used for hippocampal gene expression profiling with the Affymetrix Genechip Mouse Gene 2.0 ST Array. Array data was processed by Affymetrix Transcriptome Analysis Console (TAC) software 4.0.