Alzheimer’s disease patient-derived high-molecular-weight tau impairs bursting in hippocampal neurons by Samuel S. Harris, Robert Ellingford, instant download

Alzheimer’s disease patient-derived high-molecular-weight tau impairs bursting in hippocampal neurons by Samuel S. Harris, Robert Ellingford, instant download

SUMMARYTau accumulation is closely related to cognitive symptoms in Alzheimer’s disease (AD). However, the cellulardrivers of tau-dependent decline of memory-based cognition remain elusive. Here, we employed in vivo Neuropixels and patch-clamp recordings in mouse models and demonstrate that tau, independent of β-amyloid,selectively debilitates complex-spike burst firing of CA1 hippocampal neurons, a fundamental cellular mechanism underpinning learning and memory. Impaired bursting was associated with altered hippocampalnetwork activities that are coupled to burst firing patterns (i.e., theta rhythms and high-frequency ripples)and was concurrent with reduced neuronal expression of CaV2.3 calcium channels, which are essential forburst firing in vivo. We subsequently identify soluble high molecular weight (HMW) tau, isolated from humanAD brain, as the tau species responsible for suppression of burst firing. These data provide a cellular mechanism for tau-dependent cognitive decline in AD and implicate a rare species of intracellular HMW tau as atherapeutic target.INTRODUCTION