Statins Inhibit Fibrillary β-Amyloid Induced Inflammation in a Model of the Human Blood Brain Barrier

Abstract

BackgroundAstrocytes and cerebral endothelial cells are important components of the blood-brain barrier (BBB). Disruption to this barrier through inflammation is a major contributor to Alzheimer’s disease (AD) pathology. The amyloid beta (Aβ) protein is known to exist in several forms and is a key modulator of AD that is known to cause inflammation and changes to BBB function. While one of these forms, fibrillary Aβ (fAβ), is known to cause endothelial cell death at the BBB, no studies have looked specifically at its role on inflammation in a model of the human BBB.AimsTo determine if fAβ is inflammatory to the human BBB. As statins have been shown to be anti-inflammatory and protective in AD, we also tested if these could inhibit the inflammatory effect of fAβ.MethodsUsing cultured cerebral endothelial cells and astrocytes we determined changes in cytokine release, cell toxicity and barrier function in response to fibrillary β-amyloid1–42 (fAβ1–42) alone and in combination with statins.ResultsfAβ1–42 induced inflammatory cytokine release from endothelial cells in the absence of cell toxicity. It also induced astrocyte cytokine release and cell death and caused a loss of barrier integrity. Statin treatment inhibited all of these effects.ConclusionsWe conclude that fAβ1–42 has both inflammatory and cytotoxic effects on the BBB and the protective effect of statins in AD may in part be through inhibiting these effects.

Luteolin Inhibits Fibrillary β-Amyloid1–40-Induced Inflammation in a Human Blood-Brain Barrier Model by Suppressing the p38 MAPK-Mediated NF-κB Signaling Pathways

“…Previous studies have shown that in the BBB, high concentrations of fAβ are toxic to microvascular endothelial cells and astrocytes [ 4 , 7 , 16 ]. In the present study, changes in cell viability of hBMECs and hAs were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2 H -tetrazolium (MTS) assay.…”

“…In AD, a number of different forms of Aβ peptides are present. Monomeric, oligomeric and fibrillary Aβ toxicity to endothelial cells of cerebrovascular origin has been claimed [ 13 , 15 , 16 ]. Previous reports have shown that, in both animal models and in cell culture models, fAβ caused cell death in BBB endothelial cells [ 4 , 35 ].…”

“…In both rodents and humans, any Aβ form has been shown to have an effect on the BBB, which can lead to a cascade of events including alteration of the BBB permeability, oxidative stress, release of inflammatory components and disruption of the integrity [ 7 , 11 , 12 , 13 , 14 ]. Fibrillary Aβ (fAβ), a toxic Aβ peptide, has been shown to induce inflammatory effects on astrocytes, cerebral endothelial cells in Alzheimer brain as well as in a co-culture of these two cell types [ 4 , 5 , 15 , 16 ]. In this context, it is believed that inflammation results from Aβ toxicity, which causes the release of pro-inflammatory mediators, such as cyclooxygenase-2 (COX-2) and pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin 1 β (IL-1β).…”

Connecting the brain cholesterol and renin–angiotensin systems: potential role of statins and RAS‐modifying medications in dementia

“…Additionally, GGPP has a beneficial role in amyloid processing by regulating the active γ‐secretase complex and membrane raft association . A reduction of GGPP results in neurite loss , and this could be one of the reasons for adverse effects of statins . Other, presumably isoprenoid‐unrelated mechanisms: protective role on BBB integrity in the presence of Aβ , stimulation of neurotrophins , and mitochondrial dysfunction .…”

Antioxidants and Dementia Risk: Consideration through a Cerebrovascular Perspective

“…Similarly, simvastatin was shown to protect BBB integrity and attenuate neuropathophysiology and oxidative stress in APP transgenic AD mice [126]. In line with the latter, an in vitro study using human cerebral microvascular endothelial cells showed that simvastatin and lovastatin attenuated Aβ-induced BBB dysfunction [85]. Moreover, in a mouse model of dietary- induced BBB dysfunction, we demonstrated that atorvastatin and pravastatin reversed the disruption of BBB integrity [86].…”