Evaluation of Blood-Brain Barrier (BBB) Penetration of Alzheimer’s Drug Targets, and Identification of BBB Integrity Enhancers

The blood-brain barrier (BBB) is a highly selective membrane barrier, formed by brain endothelial cells, that separates the brain from circulating blood, preventing harmful materials in the blood from entering the
brain. BBB disruption occurs in various neurological disorders, including Alzheimer’s disease (AD), which is the most common form of dementia among older people. Therefore, there has been great interest in cell models to closely mimic human BBB function in order to understand its roles not only in normal healthy conditions but also BBB-related disorders. Supported by CAF, we developed the most physiologically relevantBBB models for use to study the role of BBB on AD pathogenesis (referred to as “3D AD-BBB monolayer model”). We think our BBB model will be of great significance to researchers investigating BBB function not only in health but also in BBB-related diseases, such as AD. We also think our model will provide a well-controlled platform for a therapeutic screening of new drugs, mimicking a human-like environment in which the drugs must pass through the BBB to get to the brain. The Cure Alzheimer’s Fund 3-D Drug Screen Consortium has finished the screening of 2,600 drugs and selected more than 38 potential AD drugs. We propose to test whether these selected drugs can pass the BBB and have effects on AD pathology in our 3D AD-BBB monolayer model. We also propose to screen compounds that reverse BBB breakdown in AD. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify the dysfunctional BBB associated with AD.