期刊
MOLECULAR PSYCHIATRY
卷 24, 期 9, 页码 1383-1397出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41380-018-0258-3
关键词
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资金
- National Institute on Aging AMP-AD [U01AG046170]
- Louis B. Mayer Foundation
- Cure Alzheimer's Fund
- Alzheimer's Disease Research Division of BrightFocus Foundation (BFFADRD) [A2018253F, A2016482F]
- Mount Sinai Alzheimer's Disease Research Center (ADRC) [P50 AG005138]
- National Institute on Aging [NIA R01AG055798]
TYROBP/DAP12 forms complexes with ectodomains of immune receptors (TREM2, SIRP beta 1, CR3) associated with Alzheimer's disease (AD) and is a network hub and driver in the complement subnetwork identified by multi-scale gene network studies of postmortem human AD brain. Using transgenic or viral approaches, we characterized in mice the effects of TYROBP deficiency on the phenotypic and pathological evolution of tauopathy. Biomarkers usually associated with worsening clinical phenotype (i.e., hyperphosphorylation and increased tauopathy spreading) were unexpectedly increased in MAPT(P301S);Tyrobp(-/-) mice despite the improved learning behavior and synaptic function relative to controls with normal levels of TYROBP. Notably, levels of complement cascade initiator C1q were reduced in MAPT(P301S);Tyrobp(-/-)mice, consistent with the prediction that C1q reduction exerts a neuroprotective effect. These observations suggest a model wherein TYROBP-KO-(knock-out)-associated reduction in C1q is associated with normalized learning behavior and electrophysiological properties in tauopathy model mice despite a paradoxical evolution of biomarker signatures usually associated with neurological decline.
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