Alzheimer’s disease (AD) has a multi­fac­to­r­ial etiol­ogy which includes, among others, vascu­lar dysfunc­tion and aberrant neuroim­mu­nity. We aim to inves­ti­gate the gene ABI3 as a poten­tial connec­tion between these two facets of AD patho­phys­i­ol­ogy. Through trans­genic murine models, and using a combi­na­tion of biochem­i­cal, immuno­his­to­chem­i­cal, and in vivo imaging techniques, we will explore how the late-onset AD risk variant S209F ABI3 affects neurode­gen­er­a­tion, immune fitness, and vascu­lar dynamics.

Alzheimer's disease (AD) is the foremost cause of demen­tia and consti­tutes a major societal and economic burden. Despite recent break­throughs, there is still no estab­lished thera­peu­tic regimen capable of stopping or revers­ing it. Given its complex multi­fac­to­r­ial nature, drug combi­na­tions hold the great­est poten­tial to achieve these goals and, among others, vascu­lar pathol­ogy and neuroim­mune dysfunc­tion are both promis­ing targets still out of thera­peu­tic reach.

We are inter­ested in the ABI3 gene, whose S209F variant carries an increased risk of devel­op­ing late-onset AD. Prelim­i­nary work has shown that trans­genic mice carry­ing the murine analog of S209F ABI3 present with microglial and neurovas­cu­lar abnor­mal­i­ties, and we believe this could be one way through which these seemingly indepen­dent mecha­nisms of disease syner­gize. In this project we aim to charac­ter­ize the biochem­istry and molec­u­lar biology of ABI3 in health and disease and, through the use of trans­genic AD murine models, detail its effects on the progres­sion of neurode­gen­er­a­tion, neuroim­mune responses, and vascu­lar dynam­ics. We will employ a combi­na­tion of biochem­istry, immuno­his­to­chem­istry on murine and human tissues, in vivo imaging of microglial motil­ity and vascu­lar responses, and multi-omics of large patient cohorts.

Overall, our work could not only help identify novel trans­la­tional targets, but also inform the adoption of clini­cal inter­ven­tions (e.g. vasopro­tec­tive measures) targeted at demen­tia patients.