Mounting clinical and experimental evidence indicates that Alzheimer Disease can be caused by vascular-related factors that directly reduce cerebral perfusion to a critical level of dysfunction. This evidence can be summarized as follows: (1) epidemiological studies show that risk factors thus far described for AD have a vascular basis; (2) most of the risk factors for AD are also associated with VaD; (3) practically all drugs reported to slow the development of AD improve or increase cerebral perfusion; (4) development of AD can be predicted preclinically by measuring regional cerebral perfusion deficits; (5) clinical evidence exists that AD symptoms are related to brain microvascular hemodynamic pathology; (6) clinical symptomatology is similar in AD and VaD; (7) cerebrovascular pathological lesions often overlap in AD and VaD; and (8) evidence that cerebral hypoperfusion appears to precede the hypometabolic, cognitive, and degenerative pathology that is present in AD.
Introduction: Reduced cerebral blood flow is associated with neurodegenerative disorders and dementia, in particular. Experimental evidence has demonstrated the initiating role of chronic cerebral hypoperfusion in neuronal damage to the hippocampus, the cerebral cortex, the white matter areas and the visual system. Permanent, bilateral occlusion of the common carotid arteries of rats (two vessel occlusion - 2VO) has been introduced for the reproduction of chronic cerebral hypoperfusion as it occurs in Alzheimer’s disease and human aging. Increased generation of free radicals through lipid peroxidation can damage neuronal cell membrane. Markers of lipid peroxidation have been found to be elevated in brain tissues and body fluids in neurodegenerative diseases, including Alzheimer’s disease, Parkinson disease and amyotrophic lateral sclerosis.
EGCG significantly suppressed the LPS-induced expression of IL-1beta and TNF-alpha in hCMECs. EGCG also inhibited the expression of MCP-1/CCL2, VCAM-1 and ICAM-1. Functional analysis showed that EGCG induced the expression of tight junction proteins (Occludin and Claudin-5) in hCMECs. Investigation of the mechanism showed that EGCG had the ability to inhibit LPS-mediated NF-kappaB activation. In addition, 67-kD laminin receptor was involved in the anti-inflammatory effect of EGCG.
Our results demonstrated that LPS induced inflammatory cytokine production in hCMECs, which could be attenuated by EGCG. These data indicate that EGCG has a therapeutic potential for endotoxin-mediated endothelial inflammation.
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