Diversity of astroglial responses across human neurodegenerative disorders and brain aging

Abstract

Astrogliopathy refers to alterations of astrocytes occurring in diseases of the nervous system, and it implies the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Reactive astrocytosis refers to the response of astrocytes to different insults to the nervous system, whereas astrocytopathy indicates hypertrophy, atrophy/degeneration and loss of function and pathological remodeling occurring as a primary cause of a disease or as a factor contributing to the development and progression of a particular disease. Reactive astrocytosis secondary to neuron loss and astrocytopathy due to intrinsic alterations of astrocytes occur in neurodegenerative diseases, overlap each other, and, together with astrocyte senescence, contribute to disease-specific astrogliopathy in aging and neurodegenerative diseases with abnormal protein aggregates in old age. In addition to the well-known increase in glial fibrillary acidic protein and other proteins in reactive astrocytes, astrocytopathy is evidenced by deposition of abnormal proteins such as β-amyloid, hyper-phosphorylated tau, abnormal α-synuclein, mutated huntingtin, phosphorylated TDP-43 and mutated SOD1, and PrP , in Alzheimer's disease, tauopathies, Lewy body diseases, Huntington's disease, amyotrophic lateral sclerosis and Creutzfeldt-Jakob disease, respectively. Astrocytopathy in these diseases can also be manifested by impaired glutamate transport; abnormal metabolism and release of neurotransmitters; altered potassium, calcium and water channels resulting in abnormal ion and water homeostasis; abnormal glucose metabolism; abnormal lipid and, particularly, cholesterol metabolism; increased oxidative damage and altered oxidative stress responses; increased production of cytokines and mediators of the inflammatory response; altered expression of connexins with deterioration of cell-to-cell networks and transfer of gliotransmitters; and worsening function of the blood brain barrier, among others. Increased knowledge of these aspects will permit a better understanding of brain aging and neurodegenerative diseases in old age as complex disorders in which neurons are not the only players.

Astrogliopathy in Tauopathies

“…GFAP is disrupted by short segments or dots of hyper-phosphorylated tau throughout the astrocytic processes in astrocytic plaques in CBD, and in astrocytes with proximal granular inclusions in FTLD-tau/P301L. Glial fibrillary acidic protein immunoreactivity is also displaced by hyper-phosphorylated tau deposits in ramified astrocytes in PiD, TSAs in ARTAG, tau-containing astrocytes in GGT, and astrocytes in familial behavioral variant frontotemporal dementia associated with astrocyte-predominant tauopathy [37,87,92] (Figure 8). .…”

“…The term astrocytopathy is used for non-reactive astrogliosis including hypertrophy, atrophy and astroglial degeneration with loss of function manifested by variable and distinct molecular changes in astrocytes, and pathological remodeling [112,117]. Senescent astrocytes are a particular form of astrocytophathy linked to old age which is manifested by modifications in the morphology of the nucleus and cytoplasm, cytoskeletal changes, oxidative damage, reduced energy production and secretory phenotype including production of inflammatory cytokines [92].…”

“…However, tau-containing astrocytes do not match reactive astrocytes and they represent different although occasionally co-existent lesions [17,18,92,124].…”

“…This suggests that generalized stress, rather than the restricted response in glial cells with abnormal protein aggregates, induces HSP expression [129]. Alternatively, it may be postulated that stress responses are directed to correcting protein misfolding, and that they succeed to a certain extent, in that aggregates are not formed in many glial cells [92]. …”

“…The localization of tau-containing astrocytes does not always match that of tau-containing neurons in tauopathies [14,19,28,76,[88][89][90][91][92]. Curiously, tufted astrocytes and astrocytic plaques are often located near the blood vessels [93], and perivascular distribution is overwhelming in a rare familial behavioral variant frontotemporal dementia associated with astrocyte-predominant tauopathy [87].…”