The ASPIRE Path in Molecular Medicine

My research plans entail investigating how APOE4, SERPINA3, and reactive glial cells contribute to the loss of blood-brain barrier (BBB) integrity and promote the pathogenesis of Alzheimer’s disease (AD) and related dementias (ADRD). APOE4 is the strongest genetic risk factor for AD and has been associated with BBB dysfunction. In humans, the SERPINA3 gene encodes the alpha 1-antichymotrypsin (ACT) protein which is a serine protease inhibitor that has been correlated with amyloid plaque formation in AD and also linked to BBB dysfunction. Therefore, we hypothesize that APOE4 may cause BBB dysfunction through a SERPINA3-dependent mechanism. We will utilize in-vitro and ex-vivo techniques and APOE4-targeted replacement mice which replace the murine APOE4 gene with the human corresponding APOE4 allele to carry out these experiments. Additionally, we will be employing iPSC-derived astrocytes since ADRD patients harbor significantly higher numbers of astrocytes. Furthermore, this research entails scRNA-sequencing to profile the relative expression of genes and signaling pathway alterations, which allows us to compare the scRNA results to disease-associated genes from human databases. Outcomes from this research will establish mechanistic links and provide valuable insight into ADRD progression that may lead to therapeutic interventions and enhance patient well-being in the future.