| Autor: |
Mann, Carolyn N., Devi, Shamulailatpam Shreedarshanee, Kersting, Corey T., Bleem, Amber V., Karch, Celeste M., Holtzman, David M., Gallardo, Gilbert |
| Předmět: |
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| Zdroj: |
Science Translational Medicine; 2/16/2022, Vol. 14 Issue 632, p1-11, 11p |
| Abstrakt: |
Alzheimer's disease (AD) is the most dominant form of dementia characterized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tau tangles (NFTs). In addition to these pathologies, an emerging pathophysiological mechanism that influences AD is neuroinflammation. Astrocytes are a vital type of glial cell that contribute to neuroinflammation, and reactive astrocytes, or astrogliosis, are a well-known pathological feature of AD. However, the mechanisms by which astrocytes contribute to the neurodegenerative process in AD have not been fully elucidated. Here, we showed that astrocytic α2-Na+/K+ adenosine triphosphatase (α2-NKA) is elevated in postmortem human brain tissue from AD and progressive nuclear palsy, a primary tauopathy. The increased astrocytic α2-NKA was also recapitulated in a mouse model of tauopathy. Pharmacological inhibition of α2-NKA robustly suppressed neuroinflammation and reduced brain atrophy. In addition, α2-NKA knockdown in tauopathy mice halted the accumulation of tau pathology. We also demonstrated that α2-NKA promoted tauopathy, in part, by regulating the proinflammatory protein lipocalin-2 (Lcn2). Overexpression of Lcn2 in tauopathy mice increased tau pathology, and prolonged Lcn2 exposure to primary neurons promoted tau uptake in vitro. These studies collectively highlight the contribution of reactive astrocytes to tau pathogenesis in mice and define α2-NKA as a major regulator of astrocytic-dependent neuroinflammation. Targeting the pump: One of the cellular hallmark of Alzheimer's disease and other tauopathies is the presence of reactive astrocytes associated with neuroinflammation and neurodegeneration. However, how astrocytes contribute to the pathophysiology of these disorders remain to be fully elucidated. Now, Mann et al. performed in vitro experiments in human tissue and in vivo studies in a mouse model and reported increased expression of the astrocytic α2-Na+/K+ ATPase (α2-NKA) in brain tissue from patients with tauopathies. In mice, pharmacological or genetic α2-NKA blockade reduced neurodegeneration by suppressing astrogliosis and reducing proinflammatory proteins including Lcn-2 which limited tau uptake. The results suggest that targeting astrocyte activation or inhibiting α2-NKA activity might be effective in reducing neurodegeneration and brain inflammation occurring in tauopathies. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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