Chimeric Antigen Receptors Discriminate Between Tau and Distinct Amyloid-Beta Species

Abstract/SummaryThe lack of a definitive cure for Alzheimers disease (AD) is fueling the search for innovative therapeutic strategies. Having revolutionized cancer immunotherapy, immune cell engineering with chimeric antigen receptors (CAR) is being explored to target AD. Whether CARs can recognize distinct amyloid-{beta} (A{beta}) species and tau neurofibrillary tangles (NFTs)--hallmark pathologies of AD--remains unclear. To investigate this, we engineered CARs based on AD antibodies targeting tau (E2814), A{beta} (Lecanemab and Aducanumab), and truncated pyroglutamate form of A{beta} (A{beta}p3-42; Donanemab and Remternetug). To evaluate CAR function, we established the murine DO11.10 hybridoma T-cell line as a practical and scalable testing platform. Our findings demonstrate that CARs can detect and discriminate between tau preformed fibrils (PFFs), A{beta}1-42, and A{beta}p3-42 aggregates. This highlights the potential of repurposing AD antibodies for CAR-based therapies to selectively target tau NFTs and distinct forms of A{beta} senile plaques.