Improving vulnerable Calbindin1- neurons in the ventral hippocampus rescues tau-induced impairment of episodic memory.

Background: Intraneuronal accumulation of hyperphosphorylated tau is a hallmark of Alzheimer's disease (AD). Given the significant correlation between tau pathology and memory loss in AD patients, identifying vulnerable brain regions, particularly susceptible neuron types in these regions, will advance our understanding of AD onset and shed light on therapeutic strategies to manage its progression.

Methods: Immunofluorescent staining was employed to identify the brain regions and neuron types vulnerable to tau pathology in AD. A combination of chemogenetics, electrophysiological recording, in vivo Ca²⁺ recording, and a modified temporal-order discrimination behavior test was utilized to investigate the toxicity of tau accumulation to susceptible neurons in the dorsal part of the ventral hippocampus. Proteomics, phosphoproteomics, and molecular targeting were used to explore the underlying mechanisms of neuron susceptibility to tau accumulation in AD. The beneficial effects of microtubule affinity regulating kinase 4 (MARK4) knockdown and administration of DEPhosphorylation TArgeting Chimera (DEPTAC) were evaluated in AD mice with tau pathology.

Results: In postmortem brains of AD patients, we observed robust accumulation of hyperphosphorylated tau in the anterior hippocampal CA1 region, particularly in its Calbindin1^- (Calb1^-) neurons, as opposed to the posterior hippocampal CA1 region and Calb1⁺ neurons. The susceptibility of Calb1^- neurons to phospho-tau accumulation was also observed in P301L mice, especially in the dorsal part of ventral (anterior in human) hippocampal CA1 (dvCA1). In P301L mice, dvCA1 displayed distinct protein and phosphorylated protein networks compared with dorsal CA1, accompanied by overactivation of MARK4. Overexpressing human tau in Calb1^- neurons in the dvCA1 (dvCA1^Calb1- neurons) specifically impairs the temporal-order discrimination of objects. Meanwhile, tau accumulation significantly inhibited the excitability and firing patterns of dvCA1^Calb1- neurons associated with temporal-order discrimination. Knocking down MARK4 or reducing hyperphosporylated tau via DEPTAC in P301L mice significantly ameliorated AD-like tau pathology in dvCA1^Calb1- neurons and improved temporal-order discrimination of objects.

Conclusion: These findings highlight the crucial role of dvCA1^Calb1- neurons in the early stage of tau pathology and demonstrate the potential of targeting phosphorylated tau through MARK4 knockdown or DEPTAC administration to counter the vulnerability of dvCA1^Calb1- neurons and, consequently, ameliorate episodic memory deficits in AD.