The importance of vascular contributions to cognitive impairment and dementia (VCID) associated with Alzheimer's disease (AD) and related neurodegenerative diseases is increasingly recognized, however, the underlying mechanisms remain obscure. There is growing evidence that in addition to Aß deposition, accumulation of hyperphosphorylated oligomeric tau contributes significantly to AD etiology. Tau oligomers are toxic and it has been suggested that they propagate in a "prion-like" fashion, inducing endogenous tau misfolding in cells. Their role in VCID, however, is not yet understood. The present study was designed to determine the severity of vascular deposition of oligomeric tau in the brain in patients with AD and related tauopathies, including dementia with Lewy bodies (DLB) and progressive supranuclear palsy (PSP). Further, we examined a potential link between vascular deposition of fibrillar Aß and that of tau oligomers in the Tg2576 mouse model. We found that tau oligomers accumulate in cerebral microvasculature of human patients with AD and PSP, in association with vascular endothelial and smooth muscle cells. Cerebrovascular deposition of tau oligomers was also found in DLB patients. We also show that tau oligomers accumulate in cerebral microvasculature of Tg2576 mice, partially in association with cerebrovascular Aß deposits. Thus, our findings add to the growing evidence for multifaceted microvascular involvement in the pathogenesis of AD and other neurodegenerative diseases. Accumulation of tau oligomers may represent a potential novel mechanism by which functional and structural integrity of the cerebral microvessels is compromised.
Bibliographical noteFunding Information:
These studies were supported by the Mitchell Center for Neurodegenerative diseases (Kayed), the National Center for Advancing Translational Sciences, National Institutes of Health, through Grants AG054025 (Kayed), NS094557 (Kayed), as well as in part by Merit Review Award I01 BX002211-01A2 from the United States Department of Veterans Affairs, Biomedical Laboratory Research and Development Service (Galvan) the San Antonio Medical Foundation (Galvan), a pilot award from the Institute for Integration of Medicine and Science UL1 TR001120 (Galvan), the JMR Barker Foundation, a William & Ella Owens Medical Research Foundation Grant (Galvan), and the generous support from the Robert L. Bailey and daughter Lisa K. Bailey Alzheimer's Fund in memory of Jo Nell Bailey to VG. We also recognize the support of the Healthspan and Functional Assesment Core of the San Antonio Nathan Shock Center of Excellence in the Biology of Aging 2 P30 AG013319-21 (Galvan) and the Oklahoma Nathan Shock Center of Excellence in the Biology of Aging 3P30AG050911-02S1 to ZU, the National Institute on Aging R01-AG047879 and R01-AG038747 (Ungvari). JBJ and CVS are supported by NIA Training Grant 2T32AG021890-11. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Copyright 2017 Elsevier B.V., All rights reserved.
All Science Journal Classification (ASJC) codes
- Pathology and Forensic Medicine
- Geriatrics and Gerontology
- Clinical Neurology
- Cell Biology