Year: 2017
Type: article
Abstract: The initiating events that promote tau mislocalization and pathology in Alzheimer's disease (AD) are not well defined, partly because of the lack of endogenous models that recapitulate tau dysfunction. We exposed wild-type neurons to a neuroinflammatory trigger and examined the effect on endogenous tau. We found that tau re-localized and accumulated within pathological neuritic foci, or beads, comprised of mostly hypo-phosphorylated, acetylated, and oligomeric tau. These structures were detected in aged wild-type mice and were enhanced in response to neuroinflammation in vivo, highlighting a previously undescribed endogenous age-related tau pathology. Strikingly, deletion or inhibition of the cytoplasmic shuttling factor HDAC6 suppressed neuritic tau bead formation in neurons and mice. Using mass spectrometry-based profiling, we identified a single neuroinflammatory factor, the metalloproteinase MMP-9, as a mediator of neuritic tau beading. Thus, our study uncovers a link between neuroinflammation and neuritic tau beading as a potential early-stage pathogenic mechanism in AD.
Source: Cell Reports
Authors: Jui-Heng Tseng, Ling Xie, Sheng Song, Youmei Xie, Lauren Allen, Deepa Ajit, Jau-Shyong Hong, Xian Chen, Rick B. Meeker, Todd J. Cohen
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Alzheimer's Association, American Federation for Aging Research, University of Pennsylvania, National Institutes of Health, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Center for Advancing Translational Sciences
Awards: G2061063643, Neural network dysfunction in early HIV neuropathogenesis, Discovery of New Innate Immune Pathways in Viral Recognition, North Carolina Translational & Clinical Sciences Institute (NC TraCS), A pathogenic role for tau acetylation in Alzheimer's disease, Neurotrophin Protection in HIV and Aging, G9000272801
OpenAlex ID: W2751317059