Endothelial Dysfunction and Repair in Alzheimer-Type Neurodegeneration: Neuronal and Glial Control

Abstract

Current theories state that Alzheimer's disease (AD) is a vascular disorder that initiates its pathology through cerebral microvascular abnormalities. Endothelial dysfunction caused by the injury or death of endothelial cells contributes to progression of AD. Also, functional relationships between neurons, glial cells, and vascular cells within so-called neurovascular unit are dramatically compromised in AD. Several recent studies have highlighted that endothelial cells might be the target for the toxic action of heavily aggregated proteins, glia-derived cytokines, and stimuli inducing oxidative and metabolic stress in AD brains. Here, we describe the properties of the brain endothelium that contribute to its specific functions in the central nervous system, and how endothelial-neuronal-glial cell interactions are compromised in the pathogenesis of AD. We also discuss the ways in which functioning of endothelial cells can be modulated in cerebral microvessels. Understanding of molecular mechanisms of endothelial injury and repair in AD would give us novel diagnostic biomarkers and pharmacological targets.

Cardiovascular risk in cognitively preserved elderlies is associated with glucose hypometabolism in the posterior cingulate cortex and precuneus regardless of brain atrophy and apolipoprotein gene variations

“…Finally, the endothelium is also a potentially relevant target for the damaging effects of CVRF, and it has been shown that functional impairment of the vascular endothelium in response to injury occurs long before the development of overt cardiovascular disease (Gimbrone 1999(Gimbrone , 2010Libby 2009). Chronic inflammatory processes, tightly linked to diseases associated with endothelial dysfunction, have been increasingly implicated as relevant to the development of the neurodegenerative changes underlying the symptoms of AD (Grammas 2000;Zlokovic 2005Zlokovic , 2010Salmina et al 2010;Grammas et al 2011b).…”

Direct Thrombin Inhibitors’ Potential Efficacy in Alzheimer’s Disease

“…6 This inflammation leads to endothelial cell activation and secretion of many cytokines and growth factors that may by themselves perpetuate cerebrovascular injury, inflammation, and neuronal death. 2,3 Role of Thrombin in Endothelial Activation of Patients With AD Brain endothelial cells in culture have been shown to synthesize thrombin under stressful conditions, such as oxidative stress with an overexpression of thrombin messenger RNA in brain endothelial cells and microvessels of patients with AD. 7,8 A possible role for thrombin in proteolysis of tau under physiological and/or pathological conditions in human brains has been suggested along with the hypothesis that phosphorylation of tau inhibits proteolysis by thrombin, leading to its aggregation into insoluble fibrils.…”

Alteration of Neuron-Glia Interactions in Neurodegeneration: Molecular Biomarkers and Therapeutic Strategy

“…In the model of focal brain ischemia in adult animals, we confirmed that CD38 could be considered as a marker of neuron-glia interactions disturbances caused by acute ischemic injury, and that modulation of ADP-ribosyl cyclase/CD38 expression and activity in the www.intechopen.com brain significantly improved clinical manifestations of neurological dysfunction associated with ischemia-induced neurodegeneration (Salmina, et al, 2006a). In patients with ischemic stroke, elevated expression of CD38 in peripheral blood leukocytes corresponds to formation of membrane-derived microparticles and progression of endothelial dysfunction due to CD38-CD31 interactions (Inzhutova et al, 2008;Salmina et al, 2010b). It is well known that astrocytes play important role in the formation, extent and configuration of the junctional complexes in the brain endothelium in a manner that astrocyte-induced enhanced tight junction communication is associated with the reduction of gap junctions.…”