Fellowship for Noah Leibold: An In Vivo Approach to Demonstrate the ApoE4-Amylin Interaction in Cerebral Edema and Microhemorrhages

Abstract: The apoE4 isoform of the APOE gene carries signi?cant risk for the development of cerebrovascular dysfunction and vascular injury, including cerebral edema and microhemorrhages. Amyloid-forming amylin secreted from the pancreas, a neuroendocrine hormone that readily crosses the blood-brain barrier (BBB), has been shown to accumulate within blood vessel walls as part of cerebral amyloid angiopathy (CAA), trigger systemic immune responses and neuroin?ammation, disrupt cerebrovascular function, reduce cerebral blood?ow (CBF), and alter neuronal metabolism. Amylin binds to circulating apolipoproteins in vivo, with a preferential affinity for APOE4. These data suggest that the interaction between bloodborne amyloid-forming amylin secreted from the pancreas and APOE4 may be a promising candidate risk factor for the mechanism by which APOE4 enhances risk for cerebral edema and microhemorrhages. In this proposal, we seek to assess the extent to which BBB injury is attributable to the amylin-APOE molecular interaction. We will cross mice humanized for amylin with mice humanized for either APOE3 or APOE4 to generate a new mouse model to recapitulate apoE-associated phenotypes under comorbid amylin-induced amyloid stress. We will use a combination of preclinical MRI techniques and biochemical assays to determine whether the presence of APOE4 under comorbid amylin cerebrovascular stress exacerbates BBB breakdown. Successful completion of the proposed aims may uncover pathways upstream of amylin interaction with the BBB which can serve as a therapeutic target to reduce cerebrovascular risk.