Tincr protects against cognitive decline by upregulating MYPT1 mediated phosphorylation of structural protein NM IIA in microglia - Research Open Access

Sep 28, 2026

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Microglial deformation and migration represent the final stages of inflammatory cytokine release and are implicated in Alzheimer’s disease (AD) pathology, yet upstream regulators remain unclear. This study shows cytoskeletal reorganization in hippocampal microglia of 2VO rats at 8 weeks and reduced Tincr expression in 2VO rats and AD patient hippocampi. Tincr knockdown increases deformation, migration, cytokines release, and phagocytic capacity, linked to NM IIA redistribution and lowered MYPT1, reversed by Tincr overexpression. Genetic rescue restores MYPT1 and attenuates deformation in 5xFAD mice. Mechanistically, Tincr upregulates MYPT1 via dual ceRNA sponging of miR-153-3p and direct MYPT1 protein scaffolding, suppressing NM IIA phosphorylation and stabilizing microglial structure. These findings define the Tincr-MYPT1-NM IIA axis in chronic cerebral hypoperfusion-induced neuroinflammation in AD.

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Introduction

Chronic cerebral hypoperfusion (CCH) and early AD/VaD relevance

Microglial activation and disease-modifying strategies

Abstract

Wang et al. Journal of Neuroinflammation (2025) 22:303 Journal of Neuroinflammation [https://doi.org/10.1186/s12974-025-03560-x](https://doi.org/10.1186/s12974-025-03560-x) RESEARCH Open Access Tincr protects against cognitive decline by upregulating MYPT1 mediated phosphorylation of structural protein NM IIAin microglia Qin Wang2,5†, Liyang Sun 1†, Jing Ma 1†, Aiping Qiu2,5†, Guitian Cong 1, Xiaobin An 1, Yang Qu 1, Mingyou Zhang 1, Xuqiao Wang 1, Lu Zeng 1, JinanYang 1, Yan Wu 1, Haining Chen 1, Jiaqi Liu 1, Fucong Han 1, Dongyang Wang 1, Tao Wang3* and Jing Ai 1,4* Abstract Microglial deformation and migration represent the final stages of inflammatory cytokines release, a key contributor to Alzheimer's disease (AD) pathology. However, the upstream regulators that initiate these morphological and functional changes in microglia remain unclear. In this study, we observed marked cytoskeletal reorganization in the hippocampal microglia of 2VO rats at 8 weeks, indicative of a shift from a homeostatic to a pro-inflammatory state. Notably, Tincr expression was significantly downregulated in both the microglia of 2VO rats and the hippocampi of AD patients. Tincr knockdown promoted microglial deformation and migration, accompanied by enhanced cytokines release and phagocytic capacity. These morphological changes correlated with redistribution of non-muscle myosin IIA ( NM IIA) and reduced expression of MYPT1, both in vitro and in vivo, effects that were reversed by Tincr overexpression. Genetic rescue of Mypt1 restored MYPT1 levels and attenuated Tincr-deficiencyinduced microglial deformation in the hippocampi of 5xFAD mice. Mechanistically, Tincr enhanced MYPT1 protein expression through dual: functioning as a competing endogenous RNA (ceRNA) that sponged miR-153- 3p, and serving as a direct protein-binding scaffold for MYPT1, thereby suppressing NM IIA phosphorylation and stabilizing microglial structure. These findings identify the Tincr-MYPT1-NM IIA axis as a critical regulatory pathway underlying chronic cerebral hypoperfusion (CCH)-induced microglial deformation and dysfunction, offering a novel mechanistic insight into the pathogenesis of neuroinflammation in AD. Keywords Chronic cerebral hypoperfusion, Cognitive impairment, Microglial cells deformation, Tincr, NM IIA, MYPT1 †Qin Wang, Liyang Sun, Jing Ma and Aiping Qiu authors contributed equally to this work. *Correspondence: Tao Wang [wangtao@ibms.pumc.edu.cn](wangtao@ibms.pumc.edu.cn)[ ](wangtao@ibms.pumc.edu.cn)Jing Ai [aijing@ems.hrbmu.edu.cn](aijing@ems.hrbmu.edu.cn); [azhrbmu@126.com](azhrbmu@126.com) 1Department of Pharmacology, The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, 157 Baojian Road, Harbin 150086, China 2Science and Technology Academic Department of Harbin Medical University Cancer Hospital, Harbin 150081, China 3Department of Human Anatomy, Institute of Basic Medical Sciences, Histology and EmbryologyJoint Laboratory of Anesthesia and Pain, School of Basic Medicine, Chinese Academy of Medical Sciences Neuroscience Center Peking Union Medical College, Beijing 100006, China 4State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), 157 Baojian Road, Harbin 150086, China 5Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin 150081, China © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party mate

FAQs

What role does Tincr play in cognitive decline and microglial function?

Tincr is significantly downregulated in microglia of 2VO rats and in hippocampi of AD patients. Modulating Tincr alters microglial deformation, migration, cytokine release, and phagocytic capacity.

How does Tincr affect the MYPT1 and NM IIA pathway?

Tincr regulates MYPT1 levels and reduces NM IIA phosphorylation. The study links Tincr-dependent morphological changes to redistribution of non-muscle myosin IIA (NM IIA) and MYPT1 downregulation, reversed by Tincr overexpression.

What evidence supports a MYPT1 rescue in mouse models?

Genetic rescue of Mypt1 restores MYPT1 levels and attenuates Tincr-deficiency-induced microglial deformation in hippocampi of 5xFAD mice.

Sep 28, 2026

Uploaded by hdkawk