The APOE-TOMM40 Humanized Mouse Model: Characterization of Age, Sex, and PolyT Variant Effects on Gene Expression

Area of Science:

• Genetics
• Neuroscience
• Pharmacology

Background:

• The 19q13.32 region of human chromosome 19 is gene-rich and linked to late-onset Alzheimer's disease (LOAD) and other age-related conditions.
• Understanding the genetic and regulatory factors influencing LOAD is crucial for developing effective treatments.

Purpose of the Study:

• To develop the first humanized mouse model encompassing the entire human TOMM40 and APOE genes, including all intronic, intergenic, and regulatory sequences.
• To investigate the impact of the TOMM40 '523' polyT genotype, sex, and age on human APOE and TOMM40 gene expression in vivo.

Main Methods:

• Generation of a humanized mouse model by replacing the mouse APOE-TOMM40 region with the human orthologs using recombineering.
• Quantification of human TOMM40 and APOE mRNA expression in mouse brain, liver, and spleen tissues via TaqMan assays.

Main Results:

• The humanized mouse model successfully expresses human TOMM40 and APOE genes.
• Significant tissue-specific and shared regulatory effects of the '523' polyT genotype, sex, and age on human TOMM40 and APOE mRNA levels were identified.
• The '523' polyT genotype demonstrated a regulatory effect across all investigated organs.

Conclusions:

• The developed humanized mouse model provides a valuable platform for studying the genetic and regulatory mechanisms of LOAD and related conditions.
• This model facilitates basic research, translational studies, and preclinical drug discovery targeting the APOE genomic region.