Role of T cells in tau-mediated neurodegeneration

Alzheimer’s disease (AD) and primary tauopathies are disorders in which the aggregation and accumulation of tau plays a key role in pathogenesis. In AD, tau aggregation and accumulation begins in the medial temporal lobe and extends into several neocortical regions just as cognitive decline begins and its progressive accumulation significantly correlates with neuronal/synaptic loss, regional brain atrophy, and neurodegeneration. Importantly, the regional presence and progression of brain atrophy and functional decline in both primary tauopathies and in AD highly correlates with tau accumulation. We have produced mice that develop tau pathology and tau-mediated neurodegeneration that are crossed onto a human APOE knockin (KI) background (P301S tau transgenic mice that express human APOE isoforms). We found that tau-mediated neurodegeneration is dependent on the presence of APOE with APOE4 resulting in greater damage than other APOE isoforms. The tau-linked neurodegeneration also requires microglia. While the tau-associated damage is dependent on the brain’s innate immune response via microglia, little is known about the extent and role of the adaptive immune responses in the presence of amyloid-β (Aβ) or tau pathology. Importantly, the contribution of the adaptive immune response to tau-mediated neurodegeneration has been unclear. We recently compared the immunological milieus in the brain of mice with amyloid deposition or tau aggregation and neurodegeneration. We found that mice with tauopathy but not amyloid, developed a unique innate and adaptive immune response and that depletion of microglia or T cells strongly attenuated tau-mediated neurodegeneration. Both CD4 and CD8 T cells were markedly increased in areas with tau pathology in P301S mice and in the AD brain. T cell numbers correlated with the extent of neuronal loss, and dynamically transformed their cellular characteristics from activated to exhausted states along with unique TCR clonal expansion. Inhibition of molecules either secreted by T cells (IFN-γ) or present on the surface of some T cells (PD-1) both significantly ameliorated brain atrophy. Our results have revealed a tauopathy and neurodegeneration-related immune hub involving activated microglia and T cell responses. Given these data, we hypothesize that understanding the role and interactions of T cells, microglia, and antigen presenting cells in tau-mediated neurodegeneration will provide novel insights into the tau-mediated pathogenesis as well as provide new therapeutic targets for preventing neurodegeneration in AD and primary tauopathies. This hypothesis will be tested in 3 Aims. Aim 1 will investigate the mechanisms underlying T cell activation and role of effector functions in microglia and T cells in tau-dependent neurodegeneration. Aim 2 will investigate potential antigen T cell receptor interactions that are relevant to T cell activation in P301S Tau Tg mice. Aim 3 will test whether different classes of clinically-approved immunosuppressant drugs that affect T cells can reduce tau pathology and neurodegeneration.