Astrocytes in Tauopathies

Abstract

Tauopathies are a group of neurodegenerative diseases characterized by the progressive accumulation across the brain of hyperphosphorylated aggregates of the microtubule-associated protein tau that vary in isoform composition, structural conformation and localization. Tau aggregates are most commonly deposited within neurons but can show differential association with astrocytes, depending on the disease. Astrocytes, the most abundant neural cells in the brain, play a major role in synapse and neuronal function, and are a key component of the glymphatic system and blood brain barrier. However, their contribution to tauopathy progression is not fully understood. Here we present a brief overview of the association of tau with astrocytes in tauopathies. We discuss findings that support a role for astrocytes in the uptake and spread of pathological tau, and we describe how alterations to astrocyte phenotype in tauopathies may cause functional alterations that impedes their ability to support neurons and/or cause neurotoxicity. The research reviewed here further highlights the importance of considering non-neuronal cells in neurodegeneration and suggests that astrocyte-directed targets that may have utility for therapeutic intervention in tauopathies.

Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction

“…Tau can be classified as 3-repeat (3R) or 4-repeat (4R), corresponding to the number of repeat domains that result from alternative splicing of exon 10 of MAPT (8)(9)(10). In adults, the ratio of 3R to 4R tau is approximately 1:1; however, certain disease mutations in the MAPT gene can cause a change in the ratio of the isoforms toward greater expression of either 3R or 4R tau (11)(12)(13). Many primary genetic MAPT mutations are found in and around exon 10, resulting in tau mis-splicing, biased 4R tau production, or mutant tau protein expression (1,14,15).…”

Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia

“…Pathological TauO triggers chronic neuroinflammation during AD, FTD, and many other tauopathies ( Guzman-Martinez et al, 2019 ; Nilson et al, 2017 ; Reid et al, 2020 ), and TauO accumulation in astrocytes may play a crucial role in pathological events ( Chun et al, 2020 ; González-Reyes et al, 2017 ; Reid et al, 2020 ). The effect of TauO on astrocytes and the underlying mechanism for TauO-induced aging-related neuroinflammation are still unknown.…”

“…Accordingly, studies have shown that astrocytes from aged mice are impaired to support neuronal growth and amyloid uptake and clearance, which leads to neurotoxicity accompanied by elevated neuroinflammatory molecules, thus contributing to progressive neuronal loss ( Iram et al, 2016 ; Kovacs, 2020 ). Chronic neuroinflammation and oxidative stress are observed in tauopathies; astrocytes seem to be involved in both, and TauO accumulation in astrocytes may play a crucial role in these pathological changes ( Chun et al, 2020 ; González-Reyes et al, 2017 ; Reid et al, 2020 ).…”

She Doesn’t Even Go Here: The Role of Inflammatory Astrocytes in CNS Disorders

“…Astrocytes have been observed to internalize tau. However, it is yet unclear whether (or when) this internalization leads to degradation or propagation of tau, and whether this contributes to the induction of an inflammatory phenotype in astrocytes (Kovacs, 2020;Reid et al, 2020;Fleeman and Proctor, 2021). In AD, the presence of reactive astrocytes often precedes the formation of the disease's characteristic histopathologies (Heneka et al, 2005;Orre et al, 2014).…”