Targeting C/EBPβ/ Calbindin 1 pathway bolsters the neural resilience to tau pathology and improves tau-impaired episodic memory.

Abstract

Intracellular accumulation of tau protein is a defining feature of Alzheimer's disease (AD) and is closely associated with episodic memory loss. In our previous report, we highlighted the high susceptibility of ventral hippocampal Calbindin1^- neurons in the dorsal part of ventral hippocampal CA1 (dvCA1^Calb1- neurons) to tau pathology in AD. However, it remains unclear whether and how dvCA1^Calb1+ neurons are also vulnerable during the chronic and progressive process of AD. In this study, we characterized dvCA1^Calb1+ neurons in terms of circuit connections and behavioral phenotypes under physiological conditions. Postmortem examination of AD patients' brains and P301L mice revealed a preferential reduction of Calb1 in the dvCA1, accompanied by heightened susceptibility of the dvCA1^Calb1+ neurons to phospho-tau mislocalization. Mechanistically, C/EBPβ was found to bind to the promoter regions of CALB1, resulting in the inhibition of CALB1 transcription. Knockdown of Calb1 accelerated, while overexpression of Calb1 impeded the AD-like tau pathology in dvCA1^Calb1+ neurons. As tau accumulated, dvCA1^Calb1+ neurons lost their firing patterns, leading to contextual social memory deficits. Ursolic acid, by promoting the degradation of C/EBPβ, modified the C/EBPβ-Calb1 pathway, ultimately enhancing the resilience of dvCA1^Calb1+ neurons against tau pathology and improving contextual social memory in AD. Our findings underscore the critical role of the C/EBPβ-Calb1 pathway in controlling the susceptibility of dvCA1^Calb1+ neurons to tau pathology. Furthermore, targeting the C/EBPβ-Calb1 pathway and UA administration could be promising strategies for treating AD in the future.