Amyloid Beta Peptides and Th1 Cytokines Modulate Human Brain Vascular Smooth Muscle Tonic Contractile Capacity In Vitro: Relevance to Alzheimer’s Disease?

Abstract

Alzheimer’s Disease (AD) is a neurodegenerative condition characterized both by the presence of tau protein neurofibrillary tangles and amyloid beta (Aβ) containing extracellular “plaques”. The cleavage of amyloid precursor protein (APP) yields several Aβ peptides. Although Aβ toxicity to neurons has been described extensively, its effects on other components of the neurovasculature such as vascular smooth muscle cells have been less well characterized. AD is now also recognized as a neurovascular disease characterized by cerebral microbleeds and disturbances in autoregulation. AD is also a neuroinflammatory condition in which several proinflammatory cytokines are elevated and may contribute to the intensification of AD severity. Cerebral autoregulation (the mechanism by which brain blood flow is maintained despite changes in perfusion pressure) is extremely tightly controlled in the brain and shows disturbances 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 might 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 gel contractility assay to evaluate the influence of Aβ 25-35, Aβ 1-40 and Aβ 1-42 peptides and inflammatory cytokines on the tonic contractility of human brain vascular smooth muscle cells (HBVSMC) as an in vitro model of cerebral autoregulation. We found that 5 and 10 μM Aβ1-42 significantly depressed HBVSM contractility, while Aβ1-40 5–20 μM had no effect on contractility. Conversely, Aβ25-35 (1–50 μM) increased contractility. Interestingly, the inflammatory cytokines TNF-α (20 ng/mL), IL-1β (20 ng/mL) and IFN- (1000 U/mL) also depressed HBVSM tonic contractility alone and in combination. These data suggest that both the inflammatory milieu in AD as well as the abundance of Aβ peptides may promote autoregulatory failure and increase brain susceptibility to dysregulated perfusion and microbleeds which are an important and devastating characteristic of AD.

Assessment of cognitive impairment after acute cerebral infarction with T1 relaxation time measured by MP2RAGE sequence and cerebral hemodynamic by transcranial Doppler

“…Endothelin and prostacyclin were the inflammatory cytokines generated during microangiopathy ( 50 ). These inflammatory cytokines interfered with the autoregulation of whole brain blood flow ( 51 ). All of the aforementioned pathophysiological alterations resulted in cerebral hypoperfusion.…”

Ranuncoside’s attenuation of scopolamine-induced memory impairment in mice via Nrf2 and NF-ĸB signaling

“…Alzheimer's disease, a complex neurodegenerative disorder, poses significant challenges, it typically progresses in old age and affects a substantial portion of the global population ( Lucey, 2020 , Serafín et al, 2020 ). The primary features of Alzheimer's disease include extracellular accumulation of amyloid beta (Aβ) peptides (i.e., Aβ1–40 and Aβ1–42) ( Gul et al, 2023 ) and intracellular accumulation of neurofibrillary tangles (i.e., insoluble hyperphosphorylated tau protein) ( Majdi et al, 2020 , Saeed et al, 2020 , Shah et al, 2015 , Winny Yun et al, 2021 ). Multiple factors have been attributed to Alzheimer's disease’s pathogenesis, therefore exact mechanism underlying this disease remains elusive ( Gadhave et al, 2021 , Uddin et al, 2020 , Wang et al, 2020 , Zhu et al, 2020 ), although, Aβ accumulation and oxidative stress are widely accepted major factors responsible for Alzheimer's disease ( Ullah et al, 2019 ).…”