Abstract
Astrocytes contribute to the pathogenesis of neurodegenerative proteinopathies as influencing neuronal degeneration or neuroprotection, and also act as potential mediators of the propagation or elimination of disease-associated proteins. Protein astrogliopathies can be observed in different forms of neurodegenerative conditions. Morphological characterization of astrogliopathy is used only for the classification of tauopathies. Currently, at least six types of astrocytic tau pathologies are distinguished. Astrocytic plaques (AP), tufted astrocytes (TAs), ramified astrocytes (RA), and globular astroglial inclusions are seen predominantly in primary tauopathies, while thorn-shaped astrocytes (TSA) and granular/fuzzy astrocytes (GFA) are evaluated in aging-related tau astrogliopathy (ARTAG). ARTAG can be seen in the white and gray matter and subpial, subependymal, and perivascular locations. Some of these overlap with the features of tau pathology seen in Chronic traumatic encephalopathy (CTE). Furthermore, gray matter ARTAG shares features with primary tauopathy-related astrocytic tau pathology. Sequential distribution patterns have been described for tau astrogliopathies. Importantly, astrocytic tau pathology in primary tauopathies can be observed in brain areas without neuronal tau deposition. The various morphologies of tau astrogliopathy might reflect a role in the propagation of pathological tau protein, an early response to a yet unidentified neurodegeneration-inducing event, or, particularly for ARTAG, a response to a repeated or prolonged pathogenic process such as blood-brain barrier dysfunction or local mechanical impact. The concept of tau astrogliopathies and ARTAG facilitated communication among research disciplines and triggered the investigation of the significance of astrocytic lesions in neurodegenerative conditions.
Highlights
CONCEPTS OF NEURODEGENERATIVE DISEASESNeurodegenerative diseases (NDDs) are characterized by progressive dysfunction of neuronal networks
Additional abnormally deposited proteins include Amyloid-β (Aβ), which is cleaved from the transmembrane amyloid precursor protein (APP), α-Synuclein, Prion protein, Transactive response (TAR) DNA-binding protein 43 (TDP-43), and FET proteins, comprising the fused in sarcoma (FUS), Ewing’s sarcoma RNA-binding protein 1 (EWSR1), and TATA-binding proteinassociated factor 15 (TAF15)
To understand the complex interaction of the tau protein and astroglia in NEURODEGENERATIVE DISEASESNeurodegenerative diseases (NDDs) the following points require consideration: (1) alterations of tau protein in disease; (2) which cell types accumulate pathological tau in different disorders; (3) how pathological tau is distributed in the human brain; (4) whether astroglia contributes to the propagation of pathological tau; and (5) whether the accumulation of tau in astroglia influence the degeneration of neurons or cause alterations in the physiological neuron-supporting roles of the astroglia
Summary
Neurodegenerative diseases (NDDs) are characterized by progressive dysfunction of neuronal networks. Analyses of glial responses should be considered in the context of comorbidities and multimorbidities Due to their crucial neuron-supporter role, astroglia reacts to the classical pathogenic events associated with NDDs, such as metabolic changes, molecular damage, and dysregulation of energetic and ion homeostasis (von Bernhardi and Eugenin, 2012). The cell-to-cell propagation theory and the recognition of sequential involvement of anatomical regions led to the description of stages and phases of pathological protein deposits (Kovacs, 2019a) These staging schemes have primarily focused on neuronal (e.g., α-synuclein in Lewy body disorders or tau for neurofibrillary tangle (NFT) formation in Alzheimer’s disease, AD) or extracellular protein deposits (e.g., Aβ in AD), without consideration of glial involvement (Liddelow and Sofroniew, 2019). To understand the complex interaction of the tau protein and astroglia in NDDs the following points require consideration: (1) alterations of tau protein in disease; (2) which cell types accumulate pathological tau in different disorders; (3) how pathological tau is distributed in the human brain; (4) whether astroglia contributes to the propagation of pathological tau; and (5) whether the accumulation of tau in astroglia influence the degeneration of neurons or cause alterations in the physiological neuron-supporting roles of the astroglia
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