Mechanobiology of the brain in ageing and Alzheimer's disease.

Chloe M Hall,Emad Moeendarbary,Graham K Sheridan

doi:10.1111/ejn.14766

Abstract

Just as the epigenome, the proteome and the electrophysiological properties of a cell influence its function, so too do its intrinsic mechanical properties and its extrinsic mechanical environment. This is especially true for neurons of the central nervous system (CNS) as long-term maintenance of synaptic connections relies on efficient axonal transport machinery and structural stability of the cytoskeleton. Recent reports suggest that profound physical changes occur in the CNS microenvironment with advancing age which, in turn, will impact highly mechanoresponsive neurons and glial cells. Here, we discuss the complex and inhomogeneous mechanical structure of CNS tissue, as revealed by recent mechanical measurements on the brain and spinal cord, using techniques such as magnetic resonance elastography and atomic force microscopy. Moreover, ageing, traumatic brain injury, demyelination and neurodegeneration can perturb the mechanical properties of brain tissue and trigger mechanobiological signalling pathways in neurons, glia and cerebral vasculature. It is, therefore, very likely that significant changes in cell and tissue mechanics contribute to age-related cognitive decline and deficits in memory formation which are accelerated and magnified in neurodegenerative states, such as Alzheimer's disease. Importantly, we are now beginning to understand how neuronal and glial cell mechanics and brain tissue mechanobiology are intimately linked with neurophysiology and cognition.

Highlights

Mechanobiology, an emerging field at the interface of biology, engineering and physics, is a rapidly expanding discipline in neuroscientific research (Jansen et al, 2015; Smith, Cho, & Discher, 2018; Xia, Pfeifer, Cho, Discher, & Irianto, 2018)
To understand and measure the mechanical properties of neurons and glia, and the forces that they experience and exert during physiological processes, engineers and biophysicists are teaming up with neurophysiologists to develop interdisciplinary approaches and techniques to advance the field (Jorba et al, 2017; Magdesian et al, 2016; Robinson, Valente, & Willerth, 2019). Such collaborations have been important for detailing the mechanical properties of different brain regions, such as the hippocampus, which is important for memory formation
We have recently shown in a transgenic rat model of Alzheimer's disease (AD) that astrocytes surrounding amyloid plaques upregulate mechanosensitive Piezo1 cation channels (Velasco-Estevez et al, 2018)

Summary

| INTRODUCTION

Mechanobiology, an emerging field at the interface of biology, engineering and physics, is a rapidly expanding discipline in neuroscientific research (Jansen et al, 2015; Smith, Cho, & Discher, 2018; Xia, Pfeifer, Cho, Discher, & Irianto, 2018). Dynamic modulus (G): It is the ratio of stress to strain when oscillatory mechanical loading is exerted on a viscoelastic material It represents both elastic and viscous behaviour of a viscoelastic material and is related to the dynamic and loss moduli through G2 = (G′)2 + (G′′). Recent studies have shown that intracellular Ca2+ flickers, mediated by Piezo channels opening at FA sites, are generated by Myosin-II phosphorylation by MLCK (Ellefsen et al, 2019) If these discrete mechanotransduction episodes were to occur in the small and narrow filopodia located at the tips of growth cones (Song et al, 2019), they may facilitate fast and transient localised signalling events that fine-tune axonal pathfinding or cell migration, for example. As the brain ages and the lipid composition of the neuronal membrane changes (Ledesma, Martin, & Dotti, 2012), this may alter the mechano-gating

| CONCLUSIONS AND FUTURE

Findings

CONFLICT OF INTEREST