Infection Augments Expression of Mechanosensing Piezo1 Channels in Amyloid Plaque-Reactive Astrocytes.

María Velasco-Estevez,Aisling Chaney,Ellie Burgess,Andrew Sharp,Graham K Sheridan,Hervé Boutin,Emad Moeendarbary,Myrthe Mampay,Kumlesh K Dev,Peter Warn

doi:10.3389/fnagi.2018.00332

Abstract

A defining pathophysiological hallmark of Alzheimer’s disease (AD) is the amyloid plaque; an extracellular deposit of aggregated fibrillar Aβ1-42 peptides. Amyloid plaques are hard, brittle structures scattered throughout the hippocampus and cerebral cortex and are thought to cause hyperphosphorylation of tau, neurofibrillary tangles, and progressive neurodegeneration. Reactive astrocytes and microglia envelop the exterior of amyloid plaques and infiltrate their inner core. Glia are highly mechanosensitive cells and can almost certainly sense the mismatch between the normally soft mechanical environment of the brain and very stiff amyloid plaques via mechanosensing ion channels. Piezo1, a non-selective cation channel, can translate extracellular mechanical forces to intracellular molecular signaling cascades through a process known as mechanotransduction. Here, we utilized an aging transgenic rat model of AD (TgF344-AD) to study expression of mechanosensing Piezo1 ion channels in amyloid plaque-reactive astrocytes. We found that Piezo1 is upregulated with age in the hippocampus and cortex of 18-month old wild-type rats. However, more striking increases in Piezo1 were measured in the hippocampus of TgF344-AD rats compared to age-matched wild-type controls. Interestingly, repeated urinary tract infections with Escherichia coli bacteria, a common comorbidity in elderly people with dementia, caused further elevations in Piezo1 channel expression in the hippocampus and cortex of TgF344-AD rats. Taken together, we report that aging and peripheral infection augment amyloid plaque-induced upregulation of mechanoresponsive ion channels, such as Piezo1, in astrocytes. Further research is required to investigate the role of astrocytic Piezo1 in the Alzheimer’s brain, whether modulating channel opening will protect or exacerbate the disease state, and most importantly, if Piezo1 could prove to be a novel drug target for age-related dementia.

Highlights

The etiology of early-onset Alzheimer’s disease (AD) has a strong genetic component and mutations in genes that encode for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) give rise to a rare but severe form of familial dementia characterized by cortical and hippocampal atrophy and progressive cognitive decline (Saunders, 2001; Nacmias et al, 2014; Lanoiselee et al, 2017)
The molecular and granule layers of the cerebellum, and non-neuronal areas of the hippocampus, express much fewer Piezo1 channels (Figures 1A,B). These regional differences were confirmed by Western blot (WB) using two distinct antibodies, i.e., one which binds the N-terminus of Piezo1 (Santa Cruz; Figures 1C,D) and one that binds the C-terminus (Abcam; Figures 1E,F)
For WB, the brains of juvenile rats were dissected into four areas, i.e., cerebellum (Crb), hippocampus (Hip), cerebral cortex (Ctx), and brain stem/thalamus (BS/T) combined

Summary

Introduction

The etiology of early-onset Alzheimer’s disease (AD) has a strong genetic component and mutations in genes that encode for amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) give rise to a rare but severe form of familial dementia characterized by cortical and hippocampal atrophy and progressive cognitive decline (Saunders, 2001; Nacmias et al, 2014; Lanoiselee et al, 2017). Astrocytes, the most abundant glial cell type in the brain, respond to amyloid plaque accumulation by adopting a ‘reactive’ phenotype characterized by an increase in intermediate filament expression, e.g., GFAP (Wilhelmsson et al, 2006; Sofroniew, 2009), and synthesis of proinflammatory cytokines (Buffo et al, 2010; Sofroniew, 2014). In addition to biochemical signals, astrogliosis in the AD brain is triggered in part by a detectable increase in the stiffness of the mechanical microenvironment experienced by resting glial cells

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