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Amyloid Beta Peptides and Inflammatory Cytokines Depress Human Brain Vascular Smooth Muscle Tonic Contractility: Relevance to Alzheimer's Disease Impaired Cerebral Autoregulation
Author(s) -
Yun J. Winny,
Washington Caretia,
Minagar Alireza,
Alexander J. Steve
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.835.2
Subject(s) - contractility , cerebral autoregulation , autoregulation , medicine , endocrinology , vasodilation , vascular smooth muscle , cerebral blood flow , amyloid beta , blood pressure , disease , smooth muscle
Alzheimer's Disease (AD) is a neurodegenerative disorder that is characterized both by the presence of tau protein neurofibrillary tangles and amyloid beta (Aβ) containing extracellular plaques. AD is also a neuroinflammatory condition in which Th1 cytokines are elevated and appear to contribute to the intensification of AD severity. The cleavage of amyloid precursor protein (APP) can result in the release of several different forms of Aβ. Although Aβ toxicity to neurons has been described extensively, stressful effects of Aβ peptides on components of the neurovasculature such as endothelial and smooth muscle cells have been less well characterized despite AD exhibiting impaired vascular properties. In particular, cerebral autoregulation, the process by which blood flow is controlled despite alterations in feeding pressure, is disturbed in AD. The failure of autoregulation in AD may make the brain susceptible to cerebral microbleeds through a reduced capacity to limit blood flow when pressure is increased. Conversely, reduced vasodilation during low flow could also exacerbate tissue hypoxia. Currently, whether and how Aβ peptides and inflammatory cytokines depress brain smooth muscle cell tonic contraction is not known, but could reveal important targets in the preservation of autoregulation which is disturbed in AD. We used a collagen contractility assay to evaluate the influence of Aβ 25–35, Aβ 1–40 and Aβ 1–42 peptides on the contractility of human brain vascular smooth muscle (HBVSM) as an in vitro model of cerebral autoregulation. We found that Aβ 1–42 significantly depressed HBVSM contractility at 5 and 10μM while 5–20μM Aβ 1–40 did not affect contractility. Conversely Aβ 25–35 increased tonic contractility at 1, 5, 10 and 20μM. Interestingly, the inflammatory cytokines TNFα (20ng/ml), IL‐1β (20ng/ml) and IFNγ (1000U/ml) also depressed HBVSM contractility. These data suggest that both the inflammatory milieu seen in AD as well as the abundance of Aβ peptides may lead to autoregulatory failure and susceptibility to cerebral microbleeds which are an important characteristic of AD. Support or Funding Information Supported by Malcolm Feist Cardiovascular Center Predoctoral Fellowship and Annette Funicello Research Foundation