Perturbed neuronal calcium homeostasis has for many years been implicated in Alzheimer's disease, and increased calcium influx has been linked to tau pathology, but this connection has not been well examined in animal models. Our preliminary studies revealed abnormal calcium activity within soma and dendrites in tauopathy mice compared to wild-type mice. Furthermore, we showed that the tau pathology-induced somatic calcium dysregulation can be reversed by acute tau antibody administration. We propose to determine how early this somatic and dendritic dysfunction occurs in tauopathy mice, its relationship to the degree of tau pathology, and the relative contribution of intra- vs. extracellular tau to these neuronal impairments. Towards this objective, the following specific aims are proposed: 1) To determine age-dependency of functional deficits within soma and dendrites in cortical tauopathy neurons with in vivo two-photon calcium imaging; 2) To determine the relative contribution of extracellular tau to neuronal calcium dysregulation compared to the total pool of tau within the brain that is accessible to antibody-mediated clearance. We hypothesize that calcium dyshomeostasis occurs earlier in dendrites than in soma, because the latter likely requires more severe neuronal dysfunction to manifest. In addition, we hypothesize that targeting both intra- and extracellular tau will be more efficacious than only targeting tau extracellularly. Our preliminary data indicates that in vivo two- photon imaging is a sensitive and comprehensive approach, within a short timeframe, to provide mechanistic insight into how tau immunotherapies work to benefit neuronal function. Using this approach, we will examine the efficacy of a tau antibody that targets tau intra- and extracellularly vs. an engineered version of the same tau antibody that is not taken up into neurons, and can only target tau extracellularly. This will allow us to determine the relative contribution of these two pools of tau on neuronal dysfunction. Overall, these studies should provide important functional and mechanistic insight into tau pathogenesis in Alzheimer's disease and related tauopathies.
The proposed project seeks to provide important functional and mechanistic insight into tau pathogenesis in Alzheimer's disease and related tauopathies. In addition, therapeutic potential will be examined for prototype antibodies with unique properties that should help in development of therapies for these diseases. Hence, this research is very relevant to public health.
