Key result
523 polyT genotype, sex, and age regulate tissue-specific TOMM40 and APOE expression in mouse models.
Why the study?
Human chromosome 19q13.32 is associated with late onset Alzheimer's disease and other age-related conditions, prompting the development of the first humanized mouse model containing the entire TOMM40 and APOE genes with their intact regulatory sequences.
The development of the APOE-TOMM40 humanized mouse model provides a new tool for studying the regulatory effects of the '523' polyT genotype, sex, and age on gene expression relevant to late-onset Alzheimer's disease.
Provides preclinical model for APOE-TOMM40 regulation; leaves open human translation in late-onset Alzheimer's.
BACKGROUND: The human chromosome 19q13.32 is a gene rich region and has been associated with multiple phenotypes, including late onset Alzheimer's disease (LOAD) and other age-related conditions. OBJECTIVE: Here we developed the first humanized mouse model that contains the entire TOMM40 and APOE genes with all intronic and intergenic sequences including the upstream and downstream regions. Thus, the mouse model carries the human TOMM40 and APOE genes and their intact regulatory sequences. METHODS: We generated the APOE-TOMM40 humanized mouse model in which the entire mouse region was replaced with the human (h)APOE-TOMM40 loci including their upstream and downstream flanking regulatory sequences using recombineering technologies. We then measured the expression of the human TOMM40 and APOE genes in the mice brain, liver, and spleen tissues using TaqMan based mRNA expression assays. RESULTS: We investigated the effects of the '523' polyT genotype (S/S or VL/VL), sex, and age on the human TOMM40- and APOE-mRNAs expression levels using our new humanized mouse model. The analysis revealed tissue specific and shared effects of the '523' polyT genotype, sex, and age on the regulation of the human TOMM40 and APOE genes. Noteworthy, the regulatory effect of the '523' polyT genotype was observed for all studied organs. CONCLUSION: The model offers new opportunities for basic science, translational, and preclinical drug discovery studies focused on the APOE genomic region in relation to LOAD and other conditions in adulthood.
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Gottschalk et al. (2023) studied Late onset Alzheimer's disease (LOAD). APOE-TOMM40 humanized mouse model was evaluated on Expression of human TOMM40 and APOE genes in brain, liver, and spleen tissues. The APOE-TOMM40 humanized mouse model demonstrated tissue-specific and shared regulatory effects of the '523' polyT genotype, sex, and age on human TOMM40 and APOE gene expression.
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