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 (dvCA1Calb1- neurons) to tau pathology in AD. However, it remains unclear whether and how dvCA1Calb1+ neurons are also vulnerable during the chronic and progressive process of AD.
In this study, we characterized dvCA1Calb1+ 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 dvCA1Calb1+ 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 dvCA1Calb1+ neurons. As tau accumulated, dvCA1Calb1+ 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 dvCA1Calb1+ 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 dvCA1Calb1+ neurons to tau pathology. Furthermore, targeting the C/EBPβ-Calb1 pathway and UA administration could be promising strategies for treating AD in the future. This is a preview of subscription content, access via your institution Receive 12 print issues and online access Prices may be subject to local taxes which are calculated during checkout Data supporting this study are available from the corresponding author upon reasonable request.
Tau-based therapies in neurodegeneration: opportunities and challenges. Nat Rev Drug Discov. 2017;16:863–83. Nature of tau-associated neurodegeneration and the molecular mechanisms.
J Alzheimers Dis. 2018;62:1305–17. CAS PubMed PubMed Central Google Scholar Baimbridge KG, Celio MR, Rogers JH. Calcium-binding proteins in the nervous system.
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