In Alzheimer's Disease (AD), tau pathology has a spatiotemporally distinct pattern of progressive spread along anatomically connected neural pathways. Extracellular tau in the brain interstitial space increases in response to neuronal activity suggesting that neural activity may also drive pathogenic tau spread. Here we tested the hypothesis that neuronal activity drives human Tau (hTau) release and trans-synaptic spread to neuroanatomically connected regions. We used AAV to overexpress wild type full-length hTau and an excitatory DREADD (Designer Receptors Exclusively Activated by a Designer Drug) in mouse primary hippocampal cultures and determined that excitatory stimulation with the DREADD ligand clozapine N-oxide (CNO) promoted extracellular hTau release. We translated this approach to an in vivo model and used AAV to express hTau and the excitatory DREADD in the ventral hippocampus of wild type mice, P301L hTau-expressing mice, or tau knockout mice. Six to eight weeks following AAV injection, we determined that CNO treatment in DREADD-expressing mice resulted in increased hTau pathology and hTau spread to distal brain regions compared to unstimulated controls (CNO in non-DREADD mice, or vehicle in DREADD mice). The results highlight a potentially disease relevant exacerbation of tau pathology in response to elevated neuronal activity. This model underscores the propensity of non-mutant hTau to undergo neuronal spreading, as seen in AD. The model can translate to other preclinical species and can be used to evaluate modes of tau transmission and test the efficacy of therapeutic approaches that target tau or hyperexcitability.
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