Soluble pathogenic tau enters brain vascular endothelial cells and drives cellular senescence and brain microvascular dysfunction in a mouse model of tauopathy
Year: 2023
Type: article
Abstract: Vascular mechanisms of Alzheimer's disease (AD) may constitute a therapeutically addressable biological pathway underlying dementia. We previously demonstrated that soluble pathogenic forms of tau (tau oligomers) accumulate in brain microvasculature of AD and other tauopathies, including prominently in microvascular endothelial cells. Here we show that soluble pathogenic tau accumulates in brain microvascular endothelial cells of P301S(PS19) mice modeling tauopathy and drives AD-like brain microvascular deficits. Microvascular impairments in P301S(PS19) mice were partially negated by selective removal of pathogenic soluble tau aggregates from brain. We found that similar to trans-neuronal transmission of pathogenic forms of tau, soluble tau aggregates are internalized by brain microvascular endothelial cells in a heparin-sensitive manner and induce microtubule destabilization, block endothelial nitric oxide synthase (eNOS) activation, and potently induce endothelial cell senescence that was recapitulated in vivo in microvasculature of P301S(PS19) mice. Our studies suggest that soluble pathogenic tau aggregates mediate AD-like brain microvascular deficits in a mouse model of tauopathy, which may arise from endothelial cell senescence and eNOS dysfunction triggered by internalization of soluble tau aggregates.
Source: Nature Communications
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,290
Funders: U.S. Department of Health and Human Services, U.S. Department of Veterans Affairs, Alzheimer's Association, American Federation for Aging Research, American Heart Association, Cancer Prevention and Research Institute of Texas, National Institutes of Health, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences
Awards: The role of proteostasis in protein aggregation in long-lived species, Oligomeric tau-induced microvascular dysfunction in Alzheimer's Disease, G1284296603, G1389313716, G1399536409, G1583363307, G1603123972, G1714969075, G1765846886, G1821512284, GEROSCIENCE TRAINING PROGRAM IN OKLAHOMA, G217228857, G2313022624, G2697612959, G2903439646, G3139818032, G3156790351, Tau-induced astrocyte senescence in Alzheimer's disease, Institute for Integration of Medicine & Science: A Partnership to Improve Health, G3678551249, G3783535814, G4217717888, G436035484, G4449996977, G4487797116, G4509790372, G4618718568, G4694532912, G4783155336, G4940311851, G5067898320, G5076088199, G5325518095, CELLULAR AND MOLECULAR GEROSCIENCE CoBRE, G5582544060, G574163375, G5746677394, G6621092144, Brain cellular senescence as a driver of Alzheimers Disease, G6953877006, G7228126214, The Role of Neuronal mTORC1 in Alzheimer's Disease, G7356373041, G7605881600, Center for Innovative Drug Discovery: Enhancement of a Shared Cancer Resource for South Texas, G7825482117, G7941599407, Oklahoma Nathan Shock Center of Excellence in Basic Biology of Aging, G815518286, G8203351351, G8402183953, G8430722030, G8619247877, G8651953381, G8871804883, NOVEL APPROACHES FOR REGULATION OF IGF-1 LEVELS THROUGHOUT THE LIFESPAN, G893528063, G9000004771, G9000025763, G9000028360, G9000038095, G9000075801, G9000087302, G9000098776, G9000148371, G9000154180, G9000157980, G9000171827, G9000183403, G9000200671, G9000268087, G9000286998, G9000340468, Formation and Propagation of Tau Oligomeric Strains in Alzheimer's Disease, G936691758
OpenAlex ID: W4366990771