Alzheimer’s genome-wide association studies (GWAS) compare the genomes of thousands of people with the disease to those without to identify genetic risk factors. These studies have shaped our understanding of the disease and identified new risk factors that warrant further investigation. Among those, Bridging Integrator 1 (BIN1) has been identified as the second most common genetic risk factor for sporadic late-onset Alzheimer’s disease (AD), trailing only behind the well-known APOE4 gene.
While researchers have primarily focused on the BIN1’s role in neurons and amyloid production, genetic evidence suggests it also influences microglial function. The mechanisms by which it does so, and how BIN1 mutations influence these functions, remain understudied. Dr. Thinakaran is an expert in BIN1 and aims to define BIN1’s role in microglia during AD.
Previously, the Thinakaran lab generated a mouse model that overexpressed BIN1 in microglia. When they crossed this model with amyloid and tau mouse models, they saw a reduction in the respective pathologies and found that the microglia did not shift into disease-associated states. This was a surprising result because when they reduced BIN1 expression in neurons, they found the same result: tau pathology was reduced. These findings suggest that BIN1’s role and influence on AD are highly dependent on whether it is found in microglia or neurons. Dr. Thinakaran hypothesizes that BIN1 keeps microglia in a balanced, healthy state, preserves their ability to clear cellular debris, and curbs inflammation in the brain.
This proposal contains two experimental aims to address this hypothesis. In the first, the Thinakaran lab will cross their microglia-specific BIN1 overexpression mouse line with a different amyloid mouse model. This new model develops amyloid pathology more gradually and at lower levels than the previous model, which produced excessive amounts of amyloid at earlier ages. They will also cross their mouse line with a mouse model of tau pathology. The Thinakaran lab will utilize advanced genetic sequencing to investigate how microglial gene activity changes in response to exposure to amyloid or tau pathology. This will help identify the communication networks within microglia and between microglia and other brain cells. The second aim will focus on defining BIN1’s role in microglia independent of pathologies and other cell types. In cultured microglia, the Thinakaran lab will examine how increasing BIN1 levels affects microglial functions, including clearing debris, recycling receptors, energy metabolism, and inflammatory signaling. This work will build the foundation for understanding BIN1’s role in microglia and inform further research on how BIN1 in these cells influences amyloid and tau pathology.
This project examines the role of a significant genetic risk factor for AD in microglia, building the foundation for further studies into effective ways to target BIN1 for potential therapies.
