| Autor: |
Mann CN; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA., Devi SS; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA., Kersting CT; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA., Bleem AV; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA., Karch CM; Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA.; Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA.; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO 63110, USA., Holtzman DM; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA.; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO 63110, USA., Gallardo G; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.; Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA. |
| 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. |
