期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 14, 期 632, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abm4107
关键词
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资金
- NIH [P01 AG03991, P30 AG066444, P01 AG026276, R56NS109007, NS090934]
- Cure Alzheimer's Fund
- JPB Foundation
- Hope Center Viral Vectors Core
- Hope Center Alafi Neuroimaging Lab
- NIH Shared Instrumentation Grant [S10 RR027552]
- NIA [P50 AG016574, R01 AG032990, U01 AG046139, R01 AG018023, U01 AG006576, U01 AG006786, R01 AG025711, R01 AG017216, R01 AG003949]
- NINDS [R01 NS080820]
- CurePSP Foundation
- Mayo Foundation
- National Institute of Neurological Disorders and Stroke [U24 NS072026]
- National Institute on Aging [P30 AG19610]
- Arizona Department of Health Services [211002]
- Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
- Michael J. Fox Foundation for Parkinsons Research
- NCI Cancer Center Support Grant [P30 CA91842]
- ICTS/CTSA Grant from the National Center for Research Resources (NCRR), a component of the NIH [UL1TR002345]
Alzheimer's disease is the most common form of dementia characterized by the deposition of amyloid plaques and neurofibrillary tau tangles. Neuroinflammation, mediated by reactive astrocytes, is an emerging pathophysiological mechanism in AD. This study demonstrates that the elevation of astrocytic alpha 2-Na+/K+ adenosine triphosphatase (alpha 2-NKA) is associated with neuroinflammation and tau pathology in AD, highlighting the important role of reactive astrocytes in the disease progression.
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 alpha 2-Na+/K+ adenosine triphosphatase (alpha 2-NKA) is elevated in postmortem human brain tissue from AD and progressive nuclear palsy, a primary tauopathy. The increased astrocytic alpha 2-NKA was also recapitulated in a mouse model of tauopathy. Pharmacological inhibition of alpha 2-NKA robustly suppressed neuroinflammation and reduced brain atrophy. In addition, alpha 2-NKA knockdown in tauopathy mice halted the accumulation of tau pathology. We also demonstrated that alpha 2-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 alpha 2-NKA as a major regulator of astrocytic-dependent neuroinflammation.
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