THERAPEUTIC EFFECT OF PD-1 IMMUNE CHECKPOINT BLOCKADE IN TAU AND AMYLOID-BETA MOUSE MODELS OF ALZHEIMER’S DISEASE

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder, which is associated with unresolved chronic neuroinflammation. Nevertheless, while immunosuppressive drugs have failed in the clinic in treating this disease, recruitment of monocytes-derived macrophages to the central nervous system (CNS) was shown to play a beneficial role in limiting disease pathology. Here, we hypothesized that systemic immune suppression might curtail the ability to mount the protective, cell-mediated immune responses that are needed for brain repair. We used the 5XFAD and human-tau (htau) double-mutant (K257T/P301S) mouse models, and tested the effect on pathology of immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway. We show in 5XFAD mice that immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway results in an IFN-gamma-dependant systemic immune response, which is followed by the recruitment of myeloid cells to the brain. When induced in mice with established pathology, PD-1 blockade leads to clearance of cerebral amyloid-beta plaques, improved cognitive performance and neuronal rescue. We further examined the effect of PD-1 blockade in the human-tau (htau) double-mutant (K257T/P301S) mouse model, demonstrating that PD-1 blockade results in improved cognitive performance in this non-amyloid AD mouse model. Our findings suggest that much like the situation in cancer immunotherapy, in order to mobilize immune cells to fight pathology, peripheral immunity should be boosted, rather than suppressed. Taken together, these findings identify immune checkpoint blockade as a novel therapeutic strategy for AD and, potentially, for other neurodegenerative diseases.