This project exemplifies the exciting collaboration fostered by CureAlz between RLG members—a leading tau-focused investigator partnering with a pioneer in macrophage engineering and chimeric mouse models. It also highlights how Alzheimer’s specialists are creatively repurposing advances in cancer and immunology.
Tau pathology—characterized by hyperphosphorylation and later neurofibrillary tau tangles—is the second hallmark of Alzheimer’s disease, alongside beta-amyloid pathology. Unlike beta-amyloid, which cells release into the extracellular matrix, tau protein resides within healthy neurons, where it maintains structural integrity, supports intracellular transport, and performs other essential functions. However, in Alzheimer’s disease (AD), tau undergoes two pathogenic changes. Early on, phosphoryl groups attach to specific locations on the protein, though the impact of this modification remains poorly understood. In other tauopathies and later stages of AD, tau detaches from cellular structures, misfolds, and forms aggregates known as neurofibrillary tangles. These tangles impair neuronal communication and ultimately lead to neurodegeneration.
Tau pathology spreads through the brain when a cell releases misfolded tau “seeds,” which neighboring cells internalize. Through a process not yet fully understood, these seeds trigger resident tau to detach and misfold in turn. Since the emergence of tau tangles strongly correlates with the onset and severity of AD symptoms, targeting and removing aggregated tau before it spreads offers a promising therapeutic approach. However, existing drug candidates targeting pathogenic tau through immunotherapies have failed in clinical trials for AD and other tauopathies. Current antibodies struggle to distinguish between harmful, aggregated tau and its normal, functional form. Even when antibodies bind to tau, effectively clearing it from the brain remains challenging. Overcoming these obstacles is critical to developing therapies that reduce tau-related brain damage and improve outcomes for individuals with Alzheimer’s and other tauopathies.
To address the limitations of tau antibodies, Dr. Diamond and Dr. Blurton-Jones drew inspiration from successful cancer immunotherapies that utilize chimeric antigen receptors (CARs). CARs are engineered proteins added to cells to create powerful immune cells capable of locating and destroying specific targets without harming healthy cells. In oncology, CARs are designed to recognize a patient’s specific cancer cells and are attached to the patient’s own T-cells. When infused into the bloodstream, these CAR-T cells harness the immune system to target and eliminate cancer cells. However, T-cells, which are part of the peripheral adaptive immune system, do not typically enter the brain.
For this project, Drs. Diamond and Blurton-Jones plan to use CARs to reprogram macrophages, a type of innate immune cell, to attack and remove tau. Macrophages from the body’s periphery regularly cross the blood-brain barrier and assume microglial housekeeping functions. Intriguingly, a prior study showed that macrophage precursor cells (monocytes) are more effective at degrading tau oligomers than central nervous system microglia. Dr. Diamond’s lab has developed an extensive library of CARs that specifically recognize pathogenic tau in Alzheimer’s and other tauopathies while sparing its functional forms. With Dr. Blurton-Jones’ expertise, these CARs were attached to macrophages to create CAR-M cells, which were further engineered to enhance the degradation and clearance of targeted tau. The team hypothesizes that administering targeted CAR-M cells at the right disease stage could prevent or remove tau pathology, thereby reducing neurodegeneration and associated clinical symptoms.
The Diamond and Blurton-Jones proposal aims to determine optimal CAR-M constructs, validate their approach in a tauopathy mouse model, and assess the efficacy of their top candidate as both a preventative and therapeutic intervention. Since no mouse model fully replicates Alzheimer’s tau pathology, they will prioritize candidates that effectively take up and degrade tau seeds from both human Alzheimer’s disease and a well-established mouse model of another tauopathy. This ensures their candidates and model are translatable. By administering CAR-M cells to mice whose microglia have been depleted, the team will evaluate whether the infused CAR-Ms successfully enter the brain and co-localize with targeted tau. Finally, they will test CAR-M therapy in mice with early-stage tau pathology to determine if it prevents further spread and in mice with advanced pathology to assess if tau burden can be meaningfully reduced.
Through this innovative approach, the Diamond and Blurton-Jones labs aim to develop therapies that not only prevent Alzheimer’s disease onset but also halt its progression in patients already experiencing its effects.
