AI Article Synopsis
- Researchers developed a humanized mouse model incorporating the human TOMM40 and APOE genes, complete with their regulatory sequences, to study late-onset Alzheimer's disease and other age-related conditions.
- The scientists employed recombineering technologies to replace the mouse gene regions with human ones, measuring gene expression in brain, liver, and spleen tissues using advanced mRNA assays.
- Their findings highlighted how factors like the '523' polyT genotype, age, and sex affect the expression of TOMM40 and APOE genes, indicating potential for new studies in drug discovery related to these genes and their implications for adult health.
Article Abstract
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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10733864 | PMC |
| http://dx.doi.org/10.3233/JAD-230451 | DOI Listing |
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