Activation of TRPV4 induces intraneuronal tau hyperphosphorylation via cholesterol accumulation

Kangshuai Du; Yunxiao Dou; Kui Chen; Yanxin Zhao

doi:10.1016/j.expneurol.2023.114392

Activation of TRPV4 induces intraneuronal tau hyperphosphorylation via cholesterol accumulation

Exp Neurol. 2023 Jun:364:114392. doi: 10.1016/j.expneurol.2023.114392. Epub 2023 Mar 28.

Authors

Kangshuai Du¹, Yunxiao Dou², Kui Chen³, Yanxin Zhao⁴

Affiliations

¹ Shanghai Clinical College, Anhui Medical University, Shanghai 200072, China; The Fifth School of Clinical Medicine, Anhui Medical University, Hefei 230032, China.
² Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China.
³ Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China. Electronic address: chenkui5457@sina.com.
⁴ Shanghai Clinical College, Anhui Medical University, Shanghai 200072, China; The Fifth School of Clinical Medicine, Anhui Medical University, Hefei 230032, China; Department of Neurology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China. Electronic address: zhao_yanxin@tongji.edu.cn.

PMID: 36990137
DOI: 10.1016/j.expneurol.2023.114392

Abstract

Transient receptor potential vanilloid 4 (TRPV4) is a non-selective cation channel, whose aberrant function in neurons has been reported to participate in the progression of brain disorders, including Alzheimer's disease (AD). However, the influence of TRPV4 activation on tau hyperphosphorylation in AD has not yet been elucidated. Since disturbed brain cholesterol homeostasis is considered to be related to excessive tau phosphorylation, this study aimed to explore whether dysregulation of TRPV4 affects tau phosphorylation and whether it involves cholesterol unbalance. Our data indicated that TRPV4 activation increased tau phosphorylation in the cortex and hippocampus of P301S tauopathy mouse model and aggravated its cognitive decline. In addition, we detected that TRPV4 activation upregulated cholesterol levels in primary neurons, and the elevation of cholesterol promoted hyperphosphorylation of tau. TRPV4 knockdown improved tau hyperphosphorylation by reducing intracellular cholesterol accumulation. Our results suggest that activation of TRPV4 may take part in the pathological mechanism of AD by promoting intraneuronal tau hyperphosphorylation in a cholesterol-dependent manner.

Keywords: Alzheimer's disease (AD); Cholesterol; Tau; Transient receptor potential vanilloid 4 (TRPV4).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / pathology
Animals
Antineoplastic Agents*
Cholesterol
Mice
Mice, Transgenic
Phosphorylation
TRPV Cation Channels / genetics
tau Proteins / metabolism

Substances

tau Proteins
TRPV Cation Channels
Antineoplastic Agents
Cholesterol
Trpv4 protein, mouse