Document Type

Article

Publication Date

9-1-2020

Keywords

JMG, JAXCC

JAX Source

Cell Rep 2020 Sep 1; 32(9):108091

PMID

32877673

DOI

https://doi.org/10.1016/j.celrep.2020.108091

Grant

AG054180; AG057914; AG063755; AG050357; AG038070; Healthspan Core; DA039841

Abstract

Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer's dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical DLGAP2 expression is observed in AD and is associated with more plaques and tangles at autopsy and faster cognitive decline. Results will inform future studies aimed at investigating the cross-species role of Dlgap2 in regulating cognitive decline and highlight the benefit of using genetically diverse mice to prioritize novel candidates.

Comments

This is an open access article under the CC BY-NC-ND license

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