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


OBJECTIVE
To 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.


METHODS
Using 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.


RESULTS
fAβ1-42 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.


CONCLUSIONS
We 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.
Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.|Department of Anatomy and Medical Imaging, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Jarred M
JM
Griffin
Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.|Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Dan
D
Kho
Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.|Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
E Scott
ES
Graham
Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.|Department of Anatomy and Medical Imaging, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Louise F B
LF
Nicholson
Centre for Brain Research, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.|Department of Anatomy and Medical Imaging, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
Simon J
SJ
O'Carroll
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008954:Models, Biological; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000924:Anticholesteremic Agents; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D015850:Interleukin-6; D016209:Interleukin-8; D008148:Lovastatin; D010446:Peptide Fragments; D019821:Simvastatin; D042461:Vascular Endothelial Growth Factor A; D000093242:Interleukin-6 Inhibitors; C111835:CCL2 protein, human; C483024:CCL5 protein, human; C508600:IL6 protein, human; C467484:VEGFA protein, human; C075222:amyloid beta-protein (1-42)