Neurovascular dysfunction, inflammation and endothelial activation: Implications for the pathogenesis of Alzheimer's disease

Garrison Institute on Aging, and Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
Journal of Neuroinflammation (Impact Factor: 5.41). 03/2011; 8(1):26. DOI: 10.1186/1742-2094-8-26
Source: PubMed


Alzheimer's disease (AD) is an age-related disorder characterized by progressive cognitive decline and dementia. Alzheimer's disease is an increasingly prevalent disease with 5.3 million people in the United States currently affected. This number is a 10 percent increase from previous estimates and is projected to sharply increase to 8 million by 2030; it is the sixth-leading cause of death. In the United States the direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $172 billion each year. Despite intense research efforts, effective disease-modifying therapies for this devastating disease remain elusive. At present, the few agents that are FDA-approved for the treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed. Although the idea that vascular defects are present in AD and may be important in disease pathogenesis was suggested over 25 years ago, little work has focused on an active role for cerebrovascular mechanisms in the pathogenesis of AD. Nevertheless, increasing literature supports a vascular-neuronal axis in AD as shared risk factors for both AD and atherosclerotic cardiovascular disease implicate vascular mechanisms in the development and/or progression of AD. Also, chronic inflammation is closely associated with cardiovascular disease, as well as a broad spectrum of neurodegenerative diseases of aging including AD. In this review we summarize data regarding, cardiovascular risk factors and vascular abnormalities, neuro- and vascular-inflammation, and brain endothelial dysfunction in AD. We conclude that the endothelial interface, a highly synthetic bioreactor that produces a large number of soluble factors, is functionally altered in AD and contributes to a noxious CNS milieu by releasing inflammatory and neurotoxic species.

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Available from: Paula Grammas, Oct 12, 2015
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    • "Vascular disease is a potentially modifiable cause of cognitive decline and dementia in older adults. Stroke, cardiovascular disease, peripheral vascular disease, hypertension, and diabetes have each been associated with cognitive deficits or dementia [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]. Although some of those diseases had markedly increased prevalence over time in AD patient admissions [e.g., type 2 diabetes (16% in 2002 to 23% in 2012), hypertension (45% in 2002 to 68% in 2012), peripheral vascular disease (4.7% to 7.6%)] and affected outcomes of hospitalization in adverse ways (e.g., congestive heart failure, pulmonary circulatory disorders), most were either unassociated with or inversely related to AD status among older patient admissions. "
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    • "Increasing evidence suggests that the neurovasculature plays an important role in the onset and progression of neurological disorders like Alzheimer's disease (AD) (Zlokovic, 2008; Grammas, 2011; Marchesi, 2014). In this regard, the concept of " neurovascular unit " , integrated by neurons, astrocytes and vascular cells, constitutes a functional unit able to maintain the homeostasis of the brain microenvironment (Iadecola, 2010). "
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    ABSTRACT: Background and purpose: Stroke and Alzheimer's disease (AD) are related pathologies in which the cerebrovascular system is involved. Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), increased in both stroke and AD patients' plasma, contributes to the vascular damage. During inflammation its enzymatic activity mediates leukocyte recruitment into the injured tissue, inducing damage in the blood-brain barrier (BBB) and neuronal tissue. We hypothesized that through the alteration of cerebrovascular function, SSAO/VAP-1 might play a role in the stroke-AD transition. Therefore, the protective effect on the BBB of the novel multitarget-directed ligand (MTDL) DPH-4, initially designed for AD therapy, was evaluated. Experimental approach: A human microvascular brain endothelial cell line expressing the human SSAO/VAP-1 (hCMEC/D3 hSSAO/VAP-1) was generated, as SSAO/VAP-1 expression is lost in cultured cells. To simulate ischemic damage, oxygen and glucose deprivation (OGD) and reoxygenation conditions were established in these cells. The protective role of DPH-4 was then evaluated in the presence of methylamine as an SSAO/VAP-1 substrate and/or β-amyloid (Aβ). Key results: Under these conditions, DPH-4 was able to protect brain endothelial cells from OGD and reoxygenation-induced damage, as well as to decrease SSAO-dependent leukocyte adhesion. DPH-4 was also effective against the damage induced by OGD and reoxygenation in the presence of Aβ as a model of AD pathology. Conclusions and implications: These results allow us to conclude that the multitarget compound DPH-4 might provide a therapeutic benefit to delay the onset and/or progression of these two linked neurological pathologies. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 09/2015; DOI:10.1111/bph.13328 · 4.84 Impact Factor
    • "Indeed, vascular smooth muscle cells treated with A 1-40 —the most frequent form of A in sporadic CAA—exhibit higher inflammatory response to interleukin-1 [134]. This cytokine is expressed by endothelial cells exposed to A 1-40 [135]. As endothelial cells are adjacent to smooth muscle cells, the above finding suggests that A could mediate the inflammatory response of smooth muscle cells, leading to the loss of contractile function through the disruption of -actin in the cytoskeleton [134]. "
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    ABSTRACT: Late-onset dementia is a major health concern in the aging population. Alzheimer's disease (AD) accounts for the largest proportion (65-70%) of dementia cases in the older population. Despite considerable research effort, the pathogenesis of late-onset AD remains unclear. Substantial evidence suggests that the neurodegenerative process is initiated by chronic cerebral hypoperfusion (CCH) caused by aging and cardiovascular conditions. CCH causes reduced oxygen, glucose and other nutrient supply to the brain, with direct damage not only to parenchymal cells, but also to the blood-brain barrier (BBB), a key mediator of cerebral homeostasis. BBB dysfunction mediates the indirect neurotoxic effects of CCH by promoting oxidative stress, inflammation, paracellular permeability, and dysregulation of nitric oxide, a key regulator of regional blood flow. As such, BBB dysfunction mediates a vicious circle in which cerebral perfusion is reduced further and the neurodegenerative process is accelerated. Endothelial interaction with pericytes and astrocytes could also play a role in the process. Reciprocal interactions between vascular dysfunction and neurodegeneration could further contribute to the development of the disease. A comprehensive overview of the complex scenario of interacting endothelium-mediated processes is currently lacking, and could prospectively contribute to the identification of adequate therapeutic interventions. This study reviews the current literature of in vitro and ex vivo studies on endothelium-mediated mechanisms underlying vascular dysfunction in AD pathogenesis, with the aim of presenting a comprehensive overview of the complex network of causative relationships. Particular emphasis is given to vicious circles which can accelerate the process of neurovascular degeneration. Copyright © 2015. Published by Elsevier Inc.
    Neurobiology of Disease 08/2015; DOI:10.1016/j.nbd.2015.08.014 · 5.08 Impact Factor
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