Genetically diverse mice reveal a mechanism of cognitive decline

Research with aging diversity outcross (DO) mice, which mimic human genetic diversity, identified variants in a gene, Dlgap2, strongly associated with the maintenance of cognitive function. Dlgap2 is a critical component of dendritic spines, neuronal structures that are essential for synaptic function. Additional investigation of human patient data revealed human DLGAP2 variants are also associated with cognitive function and dementias, indicating its importance across species and that improving dendritic spine maintenance during aging may be an important therapeutic strategy.

JAX Assistant Professor Catherine Kaczorowski, Ph.D.
Catherine Kaczorowski. JAX photo by Tiffany Lauffer.

It is widely recognized that aging is the leading risk factor for dementias such as Alzheimer’s disease. But exactly why does cognitive function decline with age in many people, but not in others? It’s a highly complex trait, and even now the mechanisms that underlie susceptibility or resilience to cognitive decline remain poorly understood.

A multi-institutional team spearheaded by the laboratory of co-senior author Jackson Laboratory (JAX) Associate Professor and including Postdoctoral Associate Niran Hadad, Ph.D.My primary research focus is on leveraging genetically diverse mouse populations to uncover genetic and epigenetic mechanisms that govern organismal cognitive agingNiran Hadad, Ph.D., also a co-senior author, and predoctoral student Andrew OuelletteInterested in cognitive resilience, genetic diversity, discovering therapeutic targets of dementia.Andrew Ouellette, turned to a recently developed resource for insight: the Diversity Outbred (DO) mouse panel. DO mice are outbred to have highly variable genetics within relatively small populations, providing a powerful tool for analyzing complex traits. Working with an aging DO mouse population (six to 18 months old), the researchers were able identify a location on chromosome 8 strongly associated with the maintenance of cognitive function. The only identified gene in the region, disk-associated large protein 2 (Dlgap2), codes for a protein that is a critical component of dendritic spines, structures on neurons in the brain that are essential for synaptic function.

In “Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer’s Dementia,” published in Cell Reports, the team uses the insight gained from the DO mice to explore the possible functional consequences of Dlgap2 variation. They characterized dendritic spine density and shape as the DO mice aged, and while younger mice showed no association between spine traits and cognitive outcomes, by 18 months they observed significant correlation with working memory performance. Their results indicate that the maintenance of thin dendritic spines (as opposed to “stubby” ones) is important for maintaining cognitive function.

Importantly, the study also reveals associations between human DLGAP2 and cognitive function and dementias. Collaborating with co-senior authors JAX Professor Elissa Chesler, Ph.D., and Vanderbilt University’s Timothy Hohman, Ph.D., the team leveraged genome-wide association studies (GWAS) of clinical Alzheimer’s disease to evaluate variants in DLGAP2 and adjacent genomic regions. They found that certain variants both within the gene and at locations that regulate its expression are associated with cognitive decline and Alzheimer’s disease. To inquire further, they looked at DLGAP2 gene expression in post-mortem human brain tissue and found that lower levels of DLGAP2 mRNA as well as its protein product correlate with faster cognitive decline as measured in clinical visits prior to death. These lower levels are also associated with Alzheimer’s disease-related neuropathologies—including greater beta-amyloid load and more neurofibrillary tangles in the brain tissue—but not non-Alzeimer’s disease traits.

The study underscores the importance of using both mouse and human resources to identify, characterize and validate genetic mechanisms that underlie complex traits. Moving forward, the DO mice will likely provide the experimental system needed to explore why dendritic spines are lost and find targets for improving their maintenance during aging. The work presented provides an important starting point for these studies, including investigating the exact role of Dlgap2 in regulating spine shape and number and maintaining cognition across species and how its genetic variants contribute to different cognitive outcomes.