This project exemplifies the high-impact, cross-disciplinary collaboration fostered by CureAlz, bringing together an expert in tau biology and a pioneer in immune cell engineering to adapt powerful strategies from cancer immunotherapy for Alzheimer’s disease (AD).
Tau tangles are one of the two hallmarks of AD. Normally, tau maintains the structural integrity of neurons and supports essential cellular functions. However, in AD, tau misfolds and forms toxic aggregates, or tangles, that impair communication between neurons and ultimately lead to cell death. Tau pathology spreads through the brain when one cell releases aggregated tau, which neighboring cells then take up. Because tau tangles are linked to the onset and severity of AD symptoms, targeting and removing aggregated tau before it invades nearby cells offers a promising treatment approach. Although preclinical models of tau immunotherapies have shown promise, the transition to clinical trials has faced significant obstacles. Current antibodies cannot distinguish between harmful, aggregated tau and its normal, functional form, and even when antibodies bind to tau, effectively clearing it from the brain remains difficult. Solving these problems is crucial for creating therapies that reduce tau-related brain damage and improve outcomes for people with Alzheimer’s and other diseases involving misfolded tau.
To tackle the current challenges with tau antibodies, Dr. Diamond and Dr. Blurton-Jones looked to successful cancer immunotherapies utilizing chimeric antigen receptors (CARs) for inspiration. CARs are engineered proteins that are added to cells to create powerful immune cells capable of locating and destroying specific targets. In cancer therapy, scientists design CARs to recognize cancer cells and then attach them to a patient’s T cells. These engineered CAR-T immune cells are then infused into the patient’s bloodstream, enabling the body’s own immune system to target and destroy cancer cells. For this project, Drs. Diamond and Blurton-Jones plan to use CARs to reprogram macrophages, another type of immune cell, to attack and remove tau. Preliminary work from Dr. Diamond’s lab produced an extensive library of CARs that specifically target pathogenic tau while sparing its functional forms. Under the expertise of Dr. Blurton-Jones, these CARs were attached to macrophages to generate CAR-M cells. By designing CAR-M cells to specifically recognize and attack toxic tau aggregates, they hypothesize that they can transform macrophages from general immune responders into specialized defenders against tau-related damage in a tauopathy mouse model.
They are investigating this hypothesis through three aims. First, they will identify which CAR-M constructs from their preliminary work best mediate tau uptake and removal in cell models. The strongest-performing CAR-M cells are then advancing to the second aim, where they are tested in mouse models. Before introducing the CAR-M cells, the teams are removing microglia from the mice to ensure that any observed effects on tau clearance are attributable to CAR-M activity. Once the CAR-M cells are introduced through the bloodstream, the labs are determining whether they can enter the brain and selectively target aggregated tau. In the third aim, the teams are evaluating CAR-M therapy both as a preventative approach and a treatment for established tau pathology by testing whether it can limit early tau accumulation or reduce advanced disease.
Since the first year of funding, the team has made strong progress toward these goals. They are identifying the most effective tau-binding components and engineering CAR-M cells that selectively recognize harmful tau while sparing healthy forms. In laboratory studies, they are demonstrating that a lead CAR-M design efficiently takes up tau aggregates and directs them to cellular “recycling” pathways for breakdown. The team has also established reliable methods to produce these engineered immune cells and has refined their strategy to support stable activity in the brain. In the coming year, they will build on this foundation by completing the remaining validation studies and advancing to animal studies to test whether optimized CAR-M therapy can enter the brain, engage with tau pathology, and slow or reverse disease progression.
If successful, this work could establish a fundamentally new approach to treating tau-driven neurodegeneration by combining precise molecular targeting with active immune-mediated clearance. This strategy has the potential to overcome key limitations of existing tau therapies and could ultimately lead to treatments that not only slow AD progression but also prevent tau pathology from spreading in the brain.
