Dysregulated Mechanotransduction in Brain Pathologies: How Physical Forces Contribute to Neurodegeneration

Mi Ri Kim¹, Ok-Hyeon Kim², Hyun Jung Lee^1,2,*
1 Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
2 Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
* Corresponding Author: Hyun Jung Lee. Email: email
(This article belongs to the Special Issue: Advanced Cell Signaling Pathways in Health and Disease)

BIOCELL https://doi.org/10.32604/biocell.2026.081123

Received 24 February 2026; Accepted 20 May 2026; Published online 04 June 2026

Download PDF

Abstract

Aging and brain injury remodel the central nervous system (CNS) physical microenvironment, yet the contribution of these mechanical changes to neurodegenerative disease remains underappreciated. While traditional models emphasize biochemical mechanisms, emerging evidence indicates that altered tissue stiffness, extracellular matrix composition, and interstitial fluid dynamics actively reprogram intracellular signaling via dysregulated mechanotransduction. This review describes key physical cues shaping the brain microenvironment, including substrate rigidity and fluid flow within the cerebrospinal fluid (CSF) and glymphatic system. We discuss how aging and injury-induced alterations disrupt mechanotransductive signaling compared to physiological conditions. Although candidate mechanosensors remain incompletely characterized, several are highlighted, including stretch-activated calcium channels like Piezo1 and Transient Receptor Potential Vanilloid 4 (TRPV4) and stiffness-responsive pathways involving focal adhesion kinase and Yes-associated protein 1 (YAP1)/Transcriptional co-activator with PDZ-binding motif (TAZ). We examine how these altered pathways influence the progression of neurodegenerative disorders and brain injury–associated pathologies. By integrating mechanobiology into neurodegenerative research, this review establishes physical forces as active disease drivers and identifies mechanotransduction as a promising frontier for the diagnosis and treatment of various brain pathologies.