Vasoactive effects of Aβ in isolated human cerebrovessels and in a transgenic mouse model of Alzheimer's disease: Role of inflammation

• Published in: Neurological research (New York) 2003-09, Vol.25 (6), p.642-651
• Main Authors: Paris, Daniel, Humphrey, James, Quadros, Amita, Patel, Nikunj, Crescentini, Robert, Crawford, Fiona, Mullan, Michael
• Format: Article
• Language: English
• Subjects: Aged; ALZHEIMER; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Animals; BETA-AMYLOID; Cerebral Arteries - metabolism; Cerebral Arteries - physiopathology; CEREBRAL BLOOD FLOW; Cerebrovascular Circulation - drug effects; Cerebrovascular Circulation - physiology; Cerebrovascular Disorders - complications; Cerebrovascular Disorders - genetics; Cerebrovascular Disorders - metabolism; CEREBROVESSELS; Cyclooxygenase 2; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis - complications; Encephalitis - genetics; Encephalitis - metabolism; Endothelin-1 - metabolism; Endothelin-1 - pharmacology; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Humans; INFLAMMATION; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Male; Membrane Proteins; Mice; Mice, Transgenic; MICROVESSEL; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; p38 Mitogen-Activated Protein Kinases; Prostaglandin-Endoperoxide Synthases - metabolism; Vasoconstriction - drug effects; Vasoconstriction - physiology
• ISSN: 0161-6412; 1743-1328
• DOI: 10.1179/016164103101201940

Aβ peptides are the major protein constituents of Alzheimer's disease (AD) senile plaques and also form some deposits in the cerebrovasculature leading to cerebral amyloid angiopathy and hemorrhagic stroke. Functional vascular abnormalities are one of the earlier clinical manifestations in both sporadic and familial forms of AD. Most of the cardiovascular risk factors (for instance, diabetes, hypertension, high cholesterol levels, atherosclerosis and smoking) constitute risk factors for AD as well, suggesting that functional vascular abnormalities may contribute to AD pathology. We studied the effect of Aβ on endothelin-1 induced vasoconstriction in isolated human cerebral arteries collected following rapid autopsies. We report that freshly solubilized Aβ enhances endothelin-1 induced vasoconstriction in isolated human middle cerebral and basilar arteries. The vasoactive effect of Aβ in these large human cerebral arteries is inhibited by NS-398, a selective cyclooxygenase-2 inhibitor and by SB202190, a specific p38 Mitogen Activated Protein Kinase inhibitor suggesting the involvement of a pro-inflammatory pathway. Using a scanner laser Doppler imager, we observed that cerebral blood flow is decreased in the double transgenic APPsw Alzheimer mouse (PS1/APPsw) compared to PS1 littermates and can be improved by chronic treatment with either NS-398 or SB202190. Altogether, our data suggest a link between inflammation and the compromised cerebral hemodynamics in AD.