Calbindin-D28k deficiency mediates tau-driven hippocampal hyperexcitement and cognitive impairment

Background Medial temporal lobe hyperexcitation or seizures originating from hippocampus are frequently observed in Alzheimer's disease (AD) patients, contributing to accelerated cognitive decline. Given the hippocampus's role as an early vulnerable area of tau pathology, a hallmark of AD, the mechanisms by which abnormal tau aggregation promotes temporal lobe epilepsy (TLE) remain poorly understood. Methods We investigated the role and mechanisms of AD-like hippocampal tau aggregation in neuronal hyperexcitation using transgenic (Tg) tau-driven mice. Tau aggregation on intracellular calcium dynamics was assessed by calcium imaging. Neuronal/network hyperexcitability and seizure susceptibility were evaluated through patch-clamp electrophysiology, ¹⁸ F-FDG PET/CT, and optogenetic induction. A tetracycline-controlled (tet-on) system in Tg hTau368 mice enabled spatiotemporal induction of tau pathology to investigate interactions with calbindin-D28k (CB) and synaptic proteins. Adeno-associated virus (AAV)-mediated CB supplementation in hippocampal CA1 and dentate gyrus (DG) excitatory neurons was tested for rescuing hyperexcitability and cognitive deficits. Finally, the relationship between CB and disease progress was analyzed using AD public database. Results Tau accumulation in hippocampal CA1/DG CaMKII-positive excitatory neurons reduced CB expression with disrupted calcium homeostasis. This dysregulation heightened neuronal excitability, diminished synaptic protein levels, and increased seizure susceptibility and cognitive impairment. AAV-driven CB restoration in CA1/DG neurons attenuated both hyperexcitability and cognitive deficits. In the brain of AD patients, the reduced CB expression was associated with cognitive deterioration and the advanced disease stages. Conclusions Tau aggregation drives CB-dependent calcium dysregulation and hippocampal neuronal hyperexcitation. These results establish a potential mechanistic link between tauopathy and TLE pathogenesis in AD, providing with CB as a promising therapeutic target for mitigating seizure risk and related cognitive decline in AD.