iPSC-derived neurovascular tissue model of cerebral amyloiad angiopathy

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Project Summary Cerebral amyloid angiopathy (CAA) is caused by the formation of beta amyloid plaques on cerebral arteries, which leads to loss of smooth muscle, vascular fragility, and intracranial hemorrhage. CAA is a risk factor for dementia independent of Alzheimer's Disease (AD), and similar to AD, no treatments are available to reverse or mitigate disease pathology. This lack of therapeutic avenues stems in part from inadequate model systems available to study the disease and identify treatment strategies. While transgenic mice have been engineered to develop certain aspects of CAA, no animal fully recapitulates the disease phenotype. Moreover, most animal models take over a year to develop the disease, and generally owing to the nature of in vivo systems, only a limited number of assays can be conducted to test drug efficacy and stratify treatment regimens. Therefore, to provide a robust, complementary resource for drug development, this proposed project focuses on constructing an in vitro human neurovascular model of CAA. This model will build upon our previous advancements in incorporating human induced pluripotent stem cell (iPSC)-derived neurovascular progenies into three- dimensional tissue constructs with representative function and appropriate spatial organization. We also introduce a novel concept for controlling CAA onset and progression using pre-templated oligomer seeds embedded in the tissue construct and a precisely delivered exogenous source of beta amyloid monomer. Aim 1 will explore concentrations of embedded oligomers and exogenous monomer to establish the kinetics of vascular amyloid deposition in acellular hydrogels. Aim 2 will incorporate relevant neurovascular cell types into the system and assess CAA pathology onset and progression under parameters established in Aim 1. Aim 3 will benchmark the observed in vitro pathology against a relevant mouse model and human tissue from CAA patients. Overall, if the in vitro system can recapitulate CAA phenotypes and reproducibly model the time course of disease progression, it will provide substantial value to the scientific community as a resource for identifying and testing drugs that will ultimately treat this devastating neurodegenerative condition.