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

Paula Grammas

Journal of Neuroinflammation · 2011 · Review

doi:10.1186/1742-2094-8-26

Abstract

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.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 17, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

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; it is the sixth-leading cause of death. 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.

The clinical entity AD has, by definition, been categorized as a "non-vascular" dementia. Widely used diagnostic criteria classify dementia as either vascular or AD-driven; despite the reality of clinical practice where vascular comorbidity may be present in 30%-60% of AD patients and, conversely, AD pathology may be present in 40%-80% of vascular dementia patients. Because of its classification as a non-vascular dementia, the role of neuro-vascular interactions in the evolution of neuronal injury in AD brain has been underappreciated. 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.

Cardiovascular risk factors in AD

Numerous studies link vascular risk factors to cognitive decline and dementia in the elderly. Old age, atherosclerosis, stroke, hypertension, transient ischemic attacks, cardiac disease, the epsilon 4 allele of the apolipoprotein E (ApoE), elevated homocysteine levels, hyperlipidemia, metabolic syndrome, obesity and diabetes are risk factors for both vascular dementia and AD. Homocysteine, considered an independent risk factor for vascular disease, has also been shown to increase the risk of AD. Several studies have shown a high correlation between cardiovascular mortality and AD and an association among hypertension, diabetes and dementia. Inheritance of the ApoE allele ε4 increases the risk of developing both atherosclerosis and late-onset AD, suggesting a vascular component to the pathogenesis of neuronal degeneration in AD. There is increasing evidence identifying a link between heart disease and AD. Heart disease is a prevalent finding in AD, and may be a forerunner to the dementing disorder. Also, increased prevalence of AD-like amyloid beta (Aβ) deposits in the neuropil and within neurons occurs in the brains of non-demented individuals with heart disease. There is a three-fold increase in risk of developing AD or vascular dementia in people with severe atherosclerosis. The large population-based Rotterdam study finds that atherosclerosis, primarily in the carotid arteries, is positively associated with the risk of developing dementia. Postmortem grading of Circle of Willis atherosclerotic lesions shows that atherosclerosis is more severe in cases with AD and vascular dementia than in non-demented controls. Finally, the idea that vascular dysfunction is a primary/central event in the pathogenesis of AD has been proposed in the context of a two-hit model of AD pathogenesis. This hypothesis postulates that neurovascular damage is a primary occurrence and that subsequent injuries including Aβ deposition amplify and/or exacerbate vascular damage which then leads to neurodegenerative processes/events and ultimately cognitive decline.

Functional and structural cerebrovascular abnormalities in AD

Abnormalities in the vascular system of the brain could contribute to the onset and/or progression of neurodegenerative events in AD. Elevated levels of markers of endothelial dysfunction (E-selectin, vascular cell adhesion molecule 1(VCAM-1)) have been determined in the plasma of older subjects with late onset AD and vascular dementia. Data from brain imaging studies in humans and animal models suggest that cerebrovascular dysfunction precedes cognitive decline and the onset of neurodegenerative changes in AD and AD animal models. Emission tomography including single photon emission computed tomography (SPECT) and positron emission tomography (PET) show AD is characterized by bilateral temporoparietal hypoperfusion on SPECT and hypometabolism on PET which precede onset of dementia. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has examined longitudinal change in glucose metabolism using [(18)F]-fluorodeoxyglucose PET (FDG-PET) and finds the use of FDG-PET as an outcome measure in clinical trials increases statistical power over traditional cognitive measurements, aids in subject selection, and reduces clinical trial sample size.

The idea that vascular defects are present in AD and may be important in disease pathogenesis was suggested over 25 years ago. The two-hit hypothesis of AD pathogenesis emphasizes the primary role of vascular defects and data linking brain endothelial cell products with neuronal cell death in AD, further support a central role for vascular abnormalities in disease pathogenesis. Numerous structural and functional cerebromicrovascular abnormalities in AD have been identified. These are atrophy and irregularities of arterioles and capillaries, swelling and increased number of pinocytotic vesicles in endothelial cells, increase in collagen IV, heparin sulfate proteolglycans and laminin deposition in the basement membrane, disruption of the basement membrane, reduced total microvascular density and occasional swelling of astrocytic end feet. Ultrastructural analysis of the blood-brain barrier in AD patients demonstrates decreased mitochondrial content, increased pinocytosis, accumulation of collagen and focal necrotic changes. Structural changes in cerebral capillaries in elderly patients correlate positively with advanced age and dementia. Also, vascular distortions such as vessel kinking, twisting, tortuosity, and looping occur in AD. Neuronal cell loss in AD may result from pathologic changes in vessel angioarchitecture, decreased cerebral blood flow, and altered oxygen utilization leading to cerebral microcirculatory impairment. Microvascular pathology displays regional and laminar patterns that parallel patterns of neuronal loss. There is a topographic association of capillaries with neuritic plaques. In addition, vascular-derived heparin sulfate proteolglycan deposits co-localize with senile plaques. A study using vascular corrosion casts to visualize the 3D arrangement of the brain vasculature, shows that in young AD animals, lacking parenchymal amyloid plaques, significant morphologic abnormalities of blood vessels are evident. Reduced staining of endothelial markers CD34 and CD31 observed in AD brains suggests that there is an extensive degeneration of the endothelium during the disease progression. Taken together, these data suggest profound vascular perturbations in AD.

Neuroinflammation, vascular inflammation and the pathogenesis of AD

Data suggest that there are important pathogenic mechanisms common to both Alzheimer's and cardiovascular disease. Chronic inflammation, characterized by elevated plasma concentrations of C reactive protein, a plasma acute-phase protein, is associated with an increased risk of atherosclerosis and has been documented in the lesions of AD. Inflammation, by definition a vascularized tissue response to injury, is a key connector linking vascular abnormalities and AD pathogenesis. A wide range of inflammatory cytokines and chemokines has been documented to play a role in the evolution of the atherosclerotic plaque. Indeed, vascular inflammation, especially of the endothelium, is central to the initiation and progression of the atherosclerosis. Chronic inflammation is associated with a broad spectrum of neurodegenerative diseases of aging including AD. Numerous studies show the presence of markers of inflammation in the AD brain. Elevated cytokines and chemokines as well as the accumulation of activated microglia are found in or near the pathologic lesions of AD. In animal models of AD lipopolysaccharide (LPS)-induced inflammation has been shown to exacerbate phosphotau pathology.

Retrospective epidemiological studies suggest that a wide variety of non-steroidal anti-inflammatory drugs (NSAIDs) may significantly reduce one's lifetime risk of developing AD. These drugs inhibit the enzymatic activity of cyclooxygenase-1 (COX-1) and inducible COX-2 which catalyze the first committed step in the synthesis of prostaglandins. Inducible COX-2 is elevated in AD; both COX-1 and 2 are involved in numerous inflammatory activities. COX inhibitors can decrease levels of highly amyloidogenic Aβ1-42 peptide. Long-term use of NSAIDs is also associated with protection from the development of AD and reduction in Aβ deposition in mouse models of AD and is positively correlated with reduction of plaque-associated microglia in both humans and mice. A meta-analysis of epidemiological data shows that NSAIDs reduce AD incidence by an average of 58%. Despite considerable animal and retrospective human studies that show beneficial effects of anti-inflammatory drugs in mitigating AD pathology, NSAIDs have failed to demonstrate therapeutic benefit in prospective AD clinical trials. No detectable effects on a variety of clinical outcome measures of AD progression are found in controlled trials of naproxen, celecoxib, and rofecoxib. Results of a clinical trial with more than 2500 participants show no significant cognitive improvement after 4 years of treatment with either naproxen or celecoxib. A large phase III trial of fluriproen recently provided no evidence of cognitive improvement in AD subjects.

Increasingly the timing of anti-inflammatory administration appears critical. The Cache county study suggests that NSAIDs help prevent cognitive decline in older adults if started in midlife rather than late life. In a study in AD transgenic mice, the reentry of neurons into the cell cycle, a pathologic feature of AD, is prevented but not reversed by NSAIDs, suggesting that inflammation is important for initiation but not the progression of the disease process. It is likely that the neurodegeneration observed in AD is the result of pathogenic processes including inflammation initiated well before the onset of cognitive symptoms associated with the disease. Recent findings suggest that alterations in production of inflammatory cytokines and chemokines are early features that precede Aβ deposition in mouse models of AD. Early expression of inflammatory mediators in the AD brain by non-neuronal cells, including endothelial cells, is likely critical to the development of disease.

In AD there is a robust elevation in inflammatory mediators in the cerebral microcirculation. AD brain endothelial cells express high levels of inflammatory adhesion molecules such as monocyte chemoattractant protein-1 (MCP-1) intercellular adhesion molecule-1 (ICAM-1) and cationic antimicrobial protein 37 kDa (CAP37). Compared to microvessels from age-matched controls, AD brain microvessels release significantly higher levels of a number of inflammatory factors including nitric oxide (NO), thrombin, tumor necrosis factor-α (TNFα), transforming growth factor-β (TGF-β), interleukin (IL) IL-1β, IL-6, IL-8, and matrix metalloproteinases (MMPs). The cerebral microvasculature is a participant in a destructive cycle of events where inflammation precedes Aβ deposition and Aβ in turn promotes release of inflammatory mediators. In this regard, exposure of brain endothelial cells to Aβ has been shown to evoke an array of pro-inflammatory responses. Aβ, via its interaction with the receptor for advanced glycation end products (RAGE) up-regulates CCR5 expression and promotes T cell migration across the blood-brain barrier. Monocytes are transported across the BBB via Aβ-RAGE-mediated signaling. Inhibitors of c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), and phosphatidylinositol 3'-kinase (PI3K) signaling cascades significantly decrease Aβ-induced CCR5 expression in human brain endothelial cells. Cultured brain endothelial cells exposed to Aβ1-40 up-regulate expression of inflammatory genes MCP-1, IL-1β, and IL-6. Quantitative RT-PCR analysis confirms elevated expression of these genes in AD and AD/CAA brains. Treatment of isolated brain microvessels with Aβ results in an increase in prostaglandin production. Cultured brain endothelial cells exposed to Aβ express CD40 and secrete interferon-gamma and IL-1β. The cerebromicrocirculation is a dynamic interface serving as both a source of, and a target for, inflammatory proteins.

Inflammation and angiogenesis: implications for AD

The mechanisms whereby inflammatory events and mediators contribute to AD pathogenesis are unclear. Specifically, the link between vascular inflammation and neuronal dysfunction and death, pathognomonic abnormalities in the AD brain, has not been defined. In the periphery, chronic inflammation as a regulator of angiogenesis has been documented. The finding that inflammation is often associated with increased angiogenesis is explained by inflammation-induced production of pro-angiogenic factors.

The possible linkage of inflammation and angiogenesis in the brain has not been widely examined in AD. However, data are emerging to support the idea that factors and processes characteristic of angiogenesis are found in the AD brain. Genome-wide expression profiling in the AD brain has identified a marked upregulation of genes that promote angiogenesis. Cerebral hypoperfusion is one of the major clinical features in AD and likely plays a critical role in its pathogenesis. Hypoxia is known to stimulate angiogenesis as well as contribute to the clinical and pathological manifestations of AD. Hypoxia causes upregulation of hypoxia-inducible genes such as vascular endothelial growth factor (VEGF). VEGF, a potent mediator of angiogenesis, is present in the AD brain in the walls of intraparenchymal vessels, diffuse perivascular deposits, and in clusters of reactive astrocytes. In addition, intrathecal levels of VEGF in AD are related to clinical severity and to intrathecal levels of Aβ. Increasing evidence suggests that polymorphisms within the promoter region of the VEGF gene may elevate the risk for AD. Brain microvessels express and release a large number of inflammatory proteins (1L-1β, IL-6, IL-8, TNFα, TGFβ, MCP-1); many of which have been implicated in angiogenesis In addition, the vasculature demonstrates up-regulation of specific molecules thought to be important regulators/markers of the angiogenic process including thrombin, VEGF, angiopoietin-2, integrins (αVβ3 αVβ5), and hypoxia inducible factor 1α (HIF-1α). The notion that inflammation and angiogenesis are interrelated molecular events is supported by studies showing that IL-1β, a major proinflammatory cytokine, can substitute for key aspects of hypoxia signaling, including induction of VEGF gene expression. This may be especially relevant for AD pathophysiology as high levels of this cytokine in AD- but not control-derived microvessels have been reported. Taken together, these data suggest a heretofore-unexplored connection between angiogenesis and AD.

Despite increases in several pro-angiogenic factors in the AD brain, evidence for increased vascularity in AD is lacking. On the contrary, it has been suggested that the angiogenic process is delayed and/or impaired in aged tissues, with several studies showing decreased microvascular density in the AD brain. Work from Mullan's group has shown that wild-type Aβ peptides have antiangiogenic effects in vitro and in vivo. Also, impaired angiogenesis has been demonstrated in AD transgenic mice. Recent data show that an amyloid peptide Aβ1-40 (E22Q), derived from individuals with the rare autosomal dominant disorder hereditary cerebral hemorrhage with amyloidosis-Dutch type, has stronger anti-angiogenic activity than wild-type Aβ peptides and is poorly cleared from the brain. This appears to be related to the increased formation of low molecular weight Aβ oligomers in the culture medium surrounding human brain microvascular endothelial cells. The notion that amyloid may serve as a "brake'" in the angiogenic process is also supported by data which show that plaque-derived amyloid inhibits brain endothelial cell proliferation in vitro. Recent genomic profiling of brain endothelial cells shows low levels of vascular-restricted mesenchyme homeobox 2 gene (MEOX2) in AD individuals lead to aberrant angiogenesis and premature pruning of capillary networks resulting in reductions in the cerebral microcirculation and that hypoxia suppresses MEOX2 expression in brain endothelial cells. Furthermore, in that study a transgenic mouse line deficient in MEOX2 gene displays vascular regression and poor Aβ clearance.

The angiogenic process is complex and involves several discrete steps beginning with endothelial activation. The activated endothelium synthesizes and secretes a large number of pro-angiogenic mediators. In physiologic angiogenesis endothelial activation is reversible and self-limiting. We propose a working model to reconcile the seemingly contradictory observations of both a large number of pro-angiogenic mediators and an absence of new vessel growth in the AD brain. In response to a persistent or intermittent stimulus, such as cerebral hypoperfusion, one of the major clinical features of AD, brain endothelial cells become activated. Activated endothelial cells are highly synthetic and release a host of factors that can affect the activation of nearby cells (i.e. astrocytes, microglia) and/or the viability of neurons. Despite the continued presence of the stimulus, no new vessel growth occurs. The inhibition of vascular growth is likely mutlifactorial and could involve the anti-angiogenic activity of Aβ, defective homeobox signaling, as well as combinations of these and other mechanisms. Because no new vessels are formed, there are no feedback signals to shut off vascular activation endothelial cells. In AD reversible endothelial activation becomes irreversible endothelial dysfunction. The vascular products of a permanently dysfunctional endothelium could cause neuronal injury. A diagram of this hypothesis is shown in Figure 1.

Results of epidemiological studies suggest that some drugs purported to have beneficial effects in AD inhibit angiogenesis. The idea that vascular inflammatory changes that promote angiogenesis have functional consequences in AD is supported by data suggesting that some of the beneficial effects of NSAIDs are linked to anti-angiogenic activity. NSAIDs might inhibit angiogenesis through several mechanisms. These drugs can directly inhibit angiogenic signaling pathways such as mitogen-activated ERK2 in endothelial cells. NSAIDs can also inhibit endothelial growth factor expression and subsequent migration. Also, the enzymes COX-1 and COX-2, targets of NSAIDs, are important regulators of angiogenesis. The efficacy of COX-2 selective inhibitors in AD treatment may be related to the inhibition of prostaglandins, NO and TNFα, all of which are important to both inflammation and angiogenesis. Thalidomide, another anti-angiogenic drug which blocks endothelial cell activation and suppresses release of VEGF and TNFα, appears protective in animal models of AD preventing memory impairment induced by Aβ. Also, statins, purported to have beneficial effects in AD, have anti-angiogenic effects.

Endothelial cell activation and neuronal injury

Endothelial cells are key modulators of inflammation and angiogenesis. The endothelium is a common target for all cardiovascular risk factors, and functional impairment of the vascular endothelium in response to injury occurs long before the development of overt disease. Chronic inflammation is tightly linked to diseases associated with endothelial dysfunction. Phenotypic modulation of endothelium to a dysfunctional state is recognized to contribute to the pathogenesis of cardiovascular diseases such as atherosclerosis. Endothelial dysfunction is also increasingly implicated in the development of neurodegenerative diseases such as AD. Brain endothelial cells regulate the neuronal milieu both by their synthetic functions as well as by their blood-brain barrier function. Therefore, disturbance in cerebrovascular metabolic or transport functions could result in a noxious neuronal environment in the AD brain.

Synthetic functions of endothelial cells in health and disease

The endothelium is a highly synthetic interface that produces a large number of soluble factors; a partial list of these products is shown in Table 1. Endothelial cell products have critical effects on neighboring cells. In the walls of large vessels endothelial cell products affect smooth muscle cell phenotype and contribute to the evolution of the atherosclerotic plaque. Vascular-derived products of a permanently dysfunctional endothelium could result in neuronal injury in neurodegenerative disease states. In the AD brain, an injured/altered brain endothelial cell releases factors that are injurious or toxic to neurons. Evidence for vascular-mediated neuronal cell death in AD is derived from studies where direct co-culture of AD microvessels with neurons or incubation of cultured neurons with conditioned medium from microvessels results in neuronal cell death. In contrast, vessels from elderly nondemented donors are significantly less lethal and brain vessels from younger donors are not neurotoxic. A study using cultured brain endothelial cells shows that exposure of these cells to the inflammatory proteins IL-1β and LPS causes release factors that kill cholinergic neurons. Also, inflammatory or oxidant injury of brain endothelial cells in vitro leads to release of the neurotoxic protease thrombin. Finally, the importance of the neurovascular unit as a mediator of neuronal damage is highlighted by a recent study where pericyte-deficient mice show an age-dependent vascular damage that precedes neurodegenerative changes and cognitive impairment.

In AD thrombin has been detected in the senile plaques, characteristic of this disease. Traumatic brain injury where neurons are exposed to high thrombin levels is associated with an increased incidence of AD. Some neurologic diseases, such as AD and PD are characterized by increased levels of both thrombin and the thrombin receptor protease-activated receptor 1 (PAR-1). Furthermore, immunoreactivity for the major brain thrombin inhibitor, protease nexin-1 is found to be significantly decreased in AD brains, particularly around blood vessels, suggesting vascular release of thrombin. Our laboratory has shown, by RT-PCR, that brain blood vessels isolated from AD patients, but not age-matched controls, synthesize thrombin. Thrombin is an example of a vascular-derived factor relevant for AD because of its pluripotent effects on inflammation, angiogenesis and neurotoxicity.

Thrombin causes endothelial activation and enhanced expression and/or release of many proinflammatory proteins including MCP-1 and ICAM-1, both of which are upregulated in the cerebrovasculature in AD. The cellular action of thrombin, potent angiogenic factor, on endothelial cells may represent an important early event in activation of the normally quiescent endothelial cells and initiation of the angiogenic cascade. In endothelial cells, thrombin induces their alignment in Matrigel, the expression and secretion of angiopoietin-2, MMPs, IL-1β, IL-8 and the up-regulation of VEGF receptors. In addition, thrombin stimulates upregulation of integrin αVβ3 expression in endothelial cells. These results are likely to be important for understanding vascular pathology in AD as vascular expression of VEGF, angiopoietin-2, MMPs, IL-1β, IL-8, and integrins are all upregulated in the AD brain.

The multifunctional protease thrombin causes neuronal cell death both in vitro and in vivo. Thrombin causes rapid tau aggregation. Intracerebroventricular administration of thrombin directly into the rat brain results in neuronal cell death, glial scarring and cognitive deficits. Activation or over-expression of the receptor PAR-1 has been shown to induce motor neurodegeneration. Thrombin exerts direct neurotoxicity by several mechanisms including reentry into the cell cycle, induction of pro-apoptotic proteins, as well as via NADPH oxidase mediated oxidative stress.

Furthermore, the paracrine effects of thrombin released from endothelial cells are also important because of the ability of thrombin to activate other CNS cells such as microglia and astrocytes. Pro-inflammatory effects of thrombin on both microglia and astrocytes have been demonstrated. Intranigral injection of thrombin injures the dopaminergic neurons in the substantia nigra via thrombin-induced microglial activation and release of nitric oxide. Thrombin has been shown to stimulate the JAK2-STAT3 signaling pathway and increase transcription of inflammation-associated genes TNFα and inducible nitric oxide synthase in microglia. In astrocytes, activation of PAR-1 by thrombin leads to increased MMP-9 expression through regulation of ERK1/2. Thus, vascular-derived thrombin may directly injure neurons or affect neuronal viability indirectly via activation of microglia and astrocytes in the neurovascular unit.

Neurovascular unit dysfunction and amyloid transport

The neurovascular unit is an emerging concept that emphasizes the interactions among glial, neuronal and vascular elements. Homeostatic signaling within the neurovascular unit is critical to normal brain function. The hemodynamic communication between neurons and the cerebrovasculature is necessary to efficiently couple CBF to neuronal activation. Dysfunctional cell-cell signaling in the neurovascular unit is increasingly implicated as characteristic feature of CNS diseases. Structural and functional integrity of the CNS depends on the coordinated activity of the neurovascular unit to not only couple neural activity to CBF but also to regulate transport across the blood-brain barrier. There is some evidence that disturbance of the functional relationships among the cells of the neurovascular unit is an early event in AD. Functional MRI studies suggest that alterations in CBF regulation in response to cognitive tasks may be a predictor of risk for developing AD.

An important function of the blood-brain barrier that may go awry in AD is regulation of the brain pool of Aβ. Brain Aβ, which is in equilibrium with plasma and CSF Aβ, is modulated by influx of soluble Aβ across the blood-brain barrier via its interaction with the receptor for advanced glycation end products (RAGE) and efflux via the low density lipoprotein receptor on brain endothelial cells. Accumulating evidence from patients and animal models of AD suggests that vulnerable brains may suffer from an increase in influx receptors (RAGE) and/or a decrease in efflux receptors (lipoprotein receptor-related protein). Multiple pathogenic cascades in the neurovascular unit may contribute to faulty clearance of amyloid across the blood-brain barrier which may amplify neuronal dysfunction and injury in AD.

Aβ has toxic effects on endothelial cells both via direct mechanisms and by inducing local inflammation. The cerebral microvasculature is central to a destructive cycle of events where inflammation precedes Aβ deposition and Aβ in turn promotes release of inflammatory mediators. The cerebrovascular-derived inflammatory protein thrombin, via stimulation of functionally active thrombin (PAR-1 and PAR-3) receptors on brain endothelial cells can further stimulate inflammatory processes in an autocrine fashion. Thrombin in vitro can stimulate production of the amyloid precursor protein (APP) and cleavage of APP into fragments that are found in amyloid plaques of AD brains. In this manner, Aβ and thrombin may combine to stimulate a deleterious feed-forward cycle resulting in neuronal cell death in AD.

Conclusions

Despite intense research efforts, the enigma that is AD continues to present daunting challenges for effective therapeutic intervention. The lack of disease-modifying therapies may, in part, be attributable to the narrow research focus employed to understand this complex disease. Most human and animal studies in the AD field reflect a "neurocentric" view and have focused on the Aβ protein as the primary neurotoxic species involved in disease pathogenesis. Because of its classification as a non-vascular dementia, the role of neuro-vascular interactions in the evolution of neuronal injury in AD brain has been underappreciated. 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. The endothelium is a common target for all cardiovascular risk factors, and functional impairment of the vascular endothelium in response to injury occurs long before the development of overt disease. Chronic inflammation, a feature of AD, is tightly linked to diseases associated with endothelial dysfunction. The cerebromicrocirculation is a dynamic interface serving as both a source of, and a target for, inflammatory proteins. Brain endothelial cells regulate the neuronal milieu both by their synthetic functions as well as by their blood-brain barrier function. Therefore, disturbance in cerebrovascular metabolic or transport functions could result in a noxious neuronal environment in the AD brain. The cerebral microvasculature is central to a destructive cycle of events where inflammation precedes Aβ deposition and Aβ in turn promotes release of inflammatory mediators. In this review we summarize data that support a new paradigm of disease pathogenesis, based on endothelial dysfunction and release of pluripotent mediators with effects on inflammation, vascular activation/angiogenesis and neurotoxicity. The activated/dysfunction brain endothelium is a novel, unexplored therapeutic target in AD.

Competing interests

The author declares that they have no competing interests.

Authors' contributions

PG wrote the manuscript and has approved the final version of the manuscript.

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  32. 32.

    Zlokovic BV Deane R Sagare AP Bell RD Winkler EA Low-density lipoprotein receptor-related protein-1: a serial clearance homeostatic mechanism controlling Alzheimer's amyloid β-peptide elimination from the brainJ Neurochem2010 11510771089

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    Grammas P A damaged microcirculation contributes to neuronal cell death in Alzheimer's diseaseNeurobiol Aging2000 21199205

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    Scheibel AB J Wertheimer and M MaroisChanges in brain capillary structure in aging and dementia1984 Alan R. Liss, Inc., New York137149in Senile Dementia Outlook for the Future

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    Davies DC Hardy JA Blood-brain barrier in aging and Alzheimer's diseaseNeurobiol Aging1988 94648

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  42. 42.

    Masters CL Beyreuther K The blood-brain barrier in Alzheimer's disease and normal agingNeurobiol Aging1988 94344

    Not in our library10.1016/s0197-4580(88)80015-0

  43. 43.

    Araki K Miyakawa T Katsuragi S Ultrastructure of senile plaque using thick sections in the brain with Alzheimer's diseaseJpn J Psychiatry Neurol1991 458589

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    de la Torre JC Mussivand T Can a disturbed brain microcirculation cause Alzheimer's disease?Neurol Res1993 15146153

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  45. 45.

    Buee L Hof PR Bouras C Delacourte A Perl DP Morrison JH Fillit HM Pathological alterations of the cerebral microvasculature in Alzheimer's disease and related dementing disordersActa Neuropathol1994 87469480

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    Dorheim MA Tracey WR Pollock JS Grammas P Nitric oxide is elevated in Alzheimer's brain microvesselsBiochem Biophys Res Comm1994 205659665

    Not in our library10.1006/bbrc.1994.2716

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    Kalaria RN Hedera P Differential degeneration of the cerebral microvasculature in Alzheimer's diseaseNeuroReport1995 6477480

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  48. 48.

    Kalaria RN Pax AB Increased collagen content of cerebral microvessels in Alzheimer's diseaseBrain Res1995 705349352

    Not in our library10.1016/0006-8993(95)01250-8

  49. 49.

    Kalaria RN Cerebral vessels in aging and Alzheimer's diseasePharmacol Ther1996 72193214

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  50. 50.

    Claudio L Ultrastructural features of the blood-brain barrier in biopsy tissue from Alzheimer's disease patientsActa Neuropathol1996 91614

    Not in our library10.1007/s004010050386

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    de la Torre JC Cerebromicrovascular pathology in Alzheimer's disease compared to normal agingGerontology1997 432643

    Not in our library10.1159/000213834

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    Grammas P Moore P Weigel PH Microvessels from Alzheimer's disease brain kill neurons in vitroAm J Pathol1999 154337342

    Not in our library10.1016/s0002-9440(10)65280-7

  53. 53.

    Farkas E Luiten PG Cerebral microvascular pathology in aging and Alzheimer's diseaseProg Neurobiol2001 64575611

    Not in our library10.1016/s0301-0082(00)00068-x

  54. 54.

    Grammas P Ovase R Inflammatory factors are elevated in brain microvessels in Alzheimer's diseaseNeurobiol Aging2001 22837842

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  55. 55.

    Grammas P Ovase R Cerebrovascular TGF-β contributes to inflammation in the Alzheimer's brainAm J Pathol2002 16015831587

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    Christov A Ottman T Hamdheydari L Grammas P Structural changes in Alzheimer's disease brain microvesselsCurrent Alz Res2008 5392395

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    Meyer EP Ulmann-Schuler A Staufenbiel M Krucker T Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's diseaseProc Natl Acad Sci USA2008 10535873592

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    Cleland SJ Sattar N Petrie JR Forouhi NG Elliott HL Connell JM Endothelial dysfunction as a possible link between C-reactive protein levels and cardiovascular diseaseClin Sci2000 988531535

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    Fay WP Linking inflammation and thrombosis: Role of C-reactive proteinWorld J Cardiol2010 2365369

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    Not in our library10.1056/nejm199901143400207

  62. 62.

    De Caterina R Massaro M Scoditti E Annunziata Carluccio M Pharmacological modulation of vascular inflammation in atherothrombosisAnn NY Acad Sci2010 12072331

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    Glass CK Saijo K Winner B Marchetto MC Gage FH Mechanisms underlying inflammation in neurodegenerationCell2010 140918934

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  64. 64.

    Cooper NR Bradt BM O'Barr S Yu JX Focal inflammation in the brain: role in Alzheimer's diseaseImmunol Res2000 21159165

    Not in our library10.1385/ir:21:2-3:159

  65. 65.

    Neuroinflammation Working GroupInflammation and Alzheimer's diseaseNeurobiol Aging2000 21383421

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  66. 66.

    Tarkowski E Cytokines in dementiaCurr Drug Targets Inflamm Allergy2002 1193200

    Not in our library10.2174/1568010023344670

  67. 67.

    McGeer EG McGeer PL Inflammatory processes in Alzheimer's diseaseProg Neuropsycholpharmacol Biol Psychiatry2003 27741749

    Not in our library10.1016/s0278-5846(03)00124-6

  68. 68.

    McGeer PL McGeer EG Inflammation and the degenerative diseases of agingAnn NY Acad Sci2004 1035104116

    Not in our library10.1196/annals.1332.007

  69. 69.

    Ho GJ Drego R Hakimian E Masliah E Mechanisms of cell signaling and inflammation in Alzheimer's diseaseCurr Drug Targets Inflamm Allergy2005 4247256

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  70. 70.

    Wyss-Coray T Inflammation in Alzheimer disease: driving force, bystander or beneficial response?Nat Med2006 1210051015

    Not in our library10.1038/nm1484

  71. 71.

    Lee YJ Han SB Nam SY Oh KW Hong JT Inflammation and Alzheimer's diseaseArch Pharm Res2010 331539155

    Not in our library10.1007/s12272-010-1006-7

  72. 72.
    LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice · 2010
    No notice
  73. 73.

    McGeer PL Schulzer M McGeer EG Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studiesNeurology1996 47425432

    Not in our library10.1212/wnl.47.2.425

  74. 74.

    Stewart WF Kawas C Corrada M Metter EJ Risk of Alzheimer's disease and duration of NSAID useNeurology1997 48626632

    Not in our library10.1212/wnl.48.3.626

  75. 75.

    Hayden KM Zandi PP Khachaturian AS Szekely CA Fotuhi M Norton MC Tschanz JT Pieper CF Corcoran C Lyketsos CG Breitner JC Welsh-Bohmer KA Cache County InvestigatorsDoes NSAID use modify cognitive trajectories in the elderly? The Cache County studyNeurology2007 69275282

    Not in our library10.1212/01.wnl.0000265223.25679.2a

  76. 76.

    Vlad SC Miller DR Kowall NW Feson DT Protective effects of NSAIDs on the development of Alzheimer's diseaseNeurology2008 7016721677

    Not in our library10.1212/01.wnl.0000311269.57716.63

  77. 77.

    Pasinetti GML From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer's disease: the role of NSAIDs and cyclooxygenase in beta-amyloidosis and clinical dementiaJ Alzheimers Dis2002 4435445

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  78. 78.

    Lim GP Yang F Chu T Chen P Beech W Teter B Tran T Ubeda O Ashe KH Frautschy SA Cole GM Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer's diseaseJ Neurosci2000 2057095714

    Not in our library10.1523/jneurosci.20-15-05709.2000

  79. 79.

    Lim GP Yang F Chu T Gahtan E Ubeda O Beech W Overmier JB Hsiao-Ashec K Frautschy SA Cole GM Ibuprofen effects on Alzheimer pathology and open field activity in APPsw transgenic miceNeurobiol Aging2001 22983991

    Not in our library10.1016/s0197-4580(01)00299-8

  80. 80.

    Etminan M Gill S Samii A Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studiesBMJ2003 327128

    Not in our library10.1136/bmj.327.7407.128

  81. 81.

    Yan Q Zhang J Liu H Babu-Khan S Vassar R Biere AL Citron M Landreth G Anti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's diseaseJ Neurosci2003 2375047509

    Not in our library10.1523/jneurosci.23-20-07504.2003

  82. 82.

    Kotilinek LA Westerman MA Wang Q Panizzon K Lim GP Simonyi A Lesne S Falinska A Younkin LH Younkin SG Rowan M Cleary J Wallis RA Sun GY Cole G Frautschy S Anwyl R Ashe KH Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticityBrain2008 131651664

    Not in our library10.1093/brain/awn008

  83. 83.

    Szekely CA Thorne JE Zandi PP Ek M Messias E Breitner JC Goodman SN Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic reviewNeuroepidemiology2004 23159169

    Not in our library10.1159/000078501

  84. 84.

    Aisen PS Schafer KA Grundman M Pfeiffer E Sano M Davis KL Farlow MR Jin S Thomas RG Thal LJ Alzheimer's Disease Cooperative StudyEffects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized clinical trialJAMA2003 28928192826

    Not in our library10.1001/jama.289.21.2819

  85. 85.

    Green RD Schneider LS Hendrix SB Zavitz KH Swabb E Safety and efficacy of tarenflurbil in subjects with mild Alzheimer's disease: results from an 18-month multi-center phase 3 trialAlzheimers Dement2008 4SupplT165

    Not in our library10.1016/j.jalz.2008.05.432

  86. 86.

    ADAPT Research GroupMartin BK Szekely C Brandt J Piantadosi S Breitner JC Craft S Evans D Green R Mullan M Cognitive function over time in the Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT): results of a randomized, controlled trial of naproxen and celecoxibArch Neurol2008 896905

    Not in our library10.1001/archneur.2008.65.7.nct70006

  87. 87.

    Zandi PP Anthony JC Hayden KM Mehta K Mayer L Breitner JC Cache County Study InvestigatorsReduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County StudyNeurology2002 59880886

    Not in our library10.1212/wnl.59.6.880

  88. 88.

    Varvel NH Bhasker K Kounnas MZ Wagner SL Yang Y Lamb BT Herrup K NSAIDS prevent, but do not reverse, neuronal cell cycle reentry in a mouse model of Alzheimer diseaseJ Clin Invest2009 11936923701

    Not in our library10.1172/jci39716

  89. 89.

    Tehranian R Hasanvan H Iverfeldt K Post C Schultzberg M Early induction of interleukin-6 mRNA in the hippocampus and cortex of APPsw transgenic mice Tg2576Neurosci Lett2001 3015458

    Not in our library10.1016/s0304-3940(01)01592-0

  90. 90.
    Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice · 2005
    No notice
  91. 91.

    Frohman EM Frohman TC Gupta S de Fourgerolles A van den Noort S Expression of intercellular adhesion molecule 1 (ICAM-1) in Alzheimer's diseaseJ Neuro Sci1991 106105111

    Not in our library10.1016/0022-510x(91)90202-i

  92. 92.

    Pereira HA Kumar P Grammas P Expression of CAP37, a novel inflammatory mediator, in Alzheimer's diseaseNeurobiol Aging1996 17753759

    Not in our library10.1016/s0197-4580(96)00118-2

  93. 93.

    Thirumangalakudi L Samany PG Owoso A Wiskar B Grammas P Angiogenic proteins are expressed by brain blood vessels in Alzheimer's diseaseJ Alzheimers Dis2006 10111118

    Not in our library10.3233/jad-2006-10114

  94. 94.

    Li M Shang DS Zhao WD Tian L Li B Fang WG Zhu L Man SM Chen YH Amyloid beta interaction with receptor for advanced glycation end products up-regulates brain endothelial CCR5 expression and promotes T cells crossing the blood-brain barrierJ Immunol2009 18257785788

    Not in our library10.4049/jimmunol.0803013

  95. 95.

    Deane R Yan SD Submamaryan RK LaRue B Jovanovic S Hogg E Welch D Manness L Lin C Yu J Zhu H Ghiso J Frangione F Stern A Schmidt AM Armstrong DL Arnold B Liliensiek B Nawroth P Hofman F Kindy M Stern D Zlokovic B RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brainNat Med2003 9907913

    Not in our library10.1038/nm890

  96. 96.

    Vukic V Callaghan D Walker D Lue LF Liu QY Couraud PO Romero IA Weksler B Stanimirovic DB Zhang W Expression of inflammatory genes induced by beta-amyloid peptides in human brain endothelial cells and in Alzheimer's brain is mediated by the JNK-AP1 signaling pathwayNeurobiol Dis2009 3495106

    Not in our library10.1016/j.nbd.2008.12.007

  97. 97.

    Paris D Townsend KP Obregon DF Humphrey j Mullan M Pro-inflammatory effort of freshly solubilized beta-amyloid peptides in the brainProstaglandins Other Lipid Mediat2002 70112

    Not in our library10.1016/s0090-6980(02)00111-9

  98. 98.

    Suo Z Tan J Placzek A Crawford F Fang C Mullan M Alzheimer's beta-amyloid peptides induce inflammatory cascade in human vascular cells: the roles of cytokines and CD40Brain Res1998 807110117

    Not in our library10.1016/s0006-8993(98)00780-x

  99. 99.

    Poveshchenko AF Konenkov VI Mechanisms and factors of angiogenesisUsp Fiziol Nauk2010 416889

    Not in our library

  100. 100.

    Sgambato A Cittadini A Inflammation and cancer: a multifaceted linkEur Rev Med Pharmacol Sci2010 14263268

    Not in our library

  101. 101.

    Pogue AI Lukiw WJ Angiogenic signaling in Alzheimer's diseaseNeuroreport2004 1515071510

    Not in our library10.1097/01.wnr.0000130539.39937.1d

  102. 102.

    Miklossy J Cerebral hypoperfusion induces cortical watershed microinfarcts which may further aggravate cognitive decline in Alzheimer's diseaseNeurol Res2003 25605610

    Not in our library10.1179/016164103101202048

  103. 103.

    Pugh CW Ratcliffe PJ Regulation of angiogenesis by hypoxia: role of the HIF systemNat Med2003 9677684

    Not in our library10.1038/nm0603-677

  104. 104.

    Yamakawa M Liu LX Date T Belanger AJ Vincent KA Akita GY Kuriyama T Cheng SH Hypoxia-inducible factor-1 mediates activation of cultured vascular endothelial cells by inducing multiple angiogenic factorsCirc Res2003 93664673

    Not in our library10.1161/01.res.0000093984.48643.d7

  105. 105.

    Kalaria RN Cohen DL Premkumar DR Nag S LaManna JC Lust WD Vascular endothelial growth factor in Alzheimer's disease and experimental ischemiaBrain Res Mol Brain Res1998 62101105

    Not in our library10.1016/s0169-328x(98)00190-9

  106. 106.

    Tarkowski E Issa R Sjogren M Wallin A Blennow K Tarkowski A Kumar P Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer's disease and vascular dementiaNeurobiol Aging2002 23237243

    Not in our library10.1016/s0197-4580(01)00285-8

  107. 107.

    Del Bo R Ghezzi S Scarpini E Bresolin N Comi GP VEGF genetic variability is associated with increased risk of developing Alzheimer's diseaseJ Neurol Sci2009 2836668

    Not in our library10.1016/j.jns.2009.02.318

  108. 108.

    Grammas P Ghatreh-Samany P Thirmangalakudi L Thrombin and Inflammatory proteins are elevated in Alzheimer's disease microvessels: Implications for disease pathogenesisJ Alzheimer Dis2006 95158

    Not in our library10.3233/jad-2006-9105

  109. 109.

    Yin X Wright J Wall T Grammas P Brain endothelial cells synthesize neurotoxic thrombin in Alzheimer's diseaseAm J Pathol2010 17616001606

    Not in our library10.2353/ajpath.2010.090406

  110. 110.

    Lukiw WJ Ottlecz A Lambrou G Grueninger M Finely J Thompson HW Bazan NG Coordinate activation of HIF-1 and NF-kappaB DNA binding and COX-2 and VEGF expression in retinal cells by hypoxiaInvest Ophthalmol Vis Sci2003 4441634170

    Not in our library10.1167/iovs.02-0655

  111. 111.

    Jellinger KA Alzheimer disease and cerebrovascular pathology: an updateJ Neural Transm2002 109813836

    Not in our library10.1007/s007020200068

  112. 112.

    Buee L Hof PR Delacourte A Brain microvascular changes in Alzheimer's disease and other dementiasAnn NY Acad Sci1997 826724

    Not in our library10.1111/j.1749-6632.1997.tb48457.x

  113. 113.

    Edelber JM Reed MJ Aging and angiogenesisFront Biosci2003 8s1199s1209

    Not in our library10.2741/1166

  114. 114.

    Paris D Townsend K Quadros A Humphrey J Sun J Brem S Wotoczek-Obadia M DelleDonne A Patel N Obregon DF Crescentini R Abdullah L Coppola D Rojiani AM Crawford F Sebti SM Mullan M Inhibition of angiogenesis by Aβ peptidesAngiogenesis2004 77585

    Not in our library10.1023/b:agen.0000037335.17717.bf

  115. 115.

    Paris D Patel N DelleDonne A Quadros A Smeed R Mullan M Impaired angiogenesis in a transgenic mouse model of cerebral amyloidosisNeurosci Lett2004 3668085

    Not in our library10.1016/j.neulet.2004.05.017

  116. 116.

    Paris D Ait-Ghezala G Mathura VS Patel N Quadros A Anti-angiogenic activity of the mutant Dutch Aβ peptide on human brain microvascular endothelial cellsMol Brain Res2005 136212230

    Not in our library10.1016/j.molbrainres.2005.02.011

  117. 117.

    Monro OR Mackic JB Yamada S Segal MB Ghiso J Maurer C Calero M Frangione B Zlokovic BV Substitution at codon 22 reduces clearance of Alzheimer's amyloid-beta peptide from the cerebrospinal fluid and prevents its transport from the central nervous system into bloodNeurobiol Aging2002 23405412

    Not in our library10.1016/s0197-4580(01)00317-7

  118. 118.

    Grammas P Botchlet T Fugate R Ball MJ Roher AE Alzheimer disease amyloid proteins inhibit brain endothelial cell proliferation in vitroDementia1995 6126130

    Not in our library10.1159/000106934

  119. 119.

    Wu Z Guo H Chow N Sallstrom J Bell RD Deane R Brooks AI Kanagala S Rubio A Sagare A Liu D Li F Armstrong D Gasiewicz T Zidovetzki R Song X Hofman F Zlokovic BV Role of the MEOX2 gene in neurovascular dysfunction in Alzheimer diseaseNat Med2005 11959965

    Not in our library10.1038/nm1287

  120. 120.

    Felmeden DC Blann AD Lip GYH Angiogenesis: basic pathophysiology and implications for diseaseEur Heart J2003 24585603

    Not in our library10.1016/s0195-668x(02)00635-8

  121. 121.

    Milkiewicz M Ispanovic E Doyle JL Haas TL Regulators of angiogenesis and strategies for their therapeutic manipulationInt J Biochem Cell Biol2006 38333357

    Not in our library10.1016/j.biocel.2005.10.006

  122. 122.

    Breitner JC Welsh KA Helms MJ Gaskell PC Gau BA Roses AD Pericak-Vance MA Saunders AM Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugsNeurobiol Aging1995 16523530

    Not in our library10.1016/0197-4580(95)00049-k

  123. 123.

    Forette F Seux ML Staessen JA Thijs L Birkenhager WH Babarskiene MR Babeanu S Bossini A Gil-Extremera B Girerd X Laks T Lilov E Moisseyev V Tuomilehto J Vanhanen H Webster J Yodfat Y Fagard R Prevention of dementia in randomized double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trialLancet1998 35213471351

    Not in our library10.1016/s0140-6736(98)03086-4

  124. 124.

    Wolozin B Kellman W Ruosseau P Celesia GG Siegel G Decreased prevalence of Alzheimer's disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitorsArch Neurol2000 5714391443

    Not in our library10.1001/archneur.57.10.1439

  125. 125.

    Vagnucci AD Jr Li WW Alzheimer's disease and angiogenesisLancet2003 361605608

    Not in our library10.1016/s0140-6736(03)12521-4

  126. 126.

    Lema MJ Emerging options with coxib therapyCleve Clin J Med2002 69Suppl 1S176S184

    Not in our library10.3949/ccjm.69.suppl_1.si76

  127. 127.

    Martel-Pelletier J Pelletier JP Fahmi H Cyclooxygenase-2 and prostaglandins in articular tissuesSemin Arthritis Rheum2003 3315516740

    Not in our library10.1016/s0049-0172(03)00134-3

  128. 128.

    De Filippis D Cipriano M Esposito G Scuderi C Steardo L Iuvone T Are anti-angiogenic drugs useful in neurodegenerative disorders?CNS & Neurological Disorders - Drug Targets2010 9807812

    Not in our library10.2174/187152710793237485

  129. 129.

    Jones MK Wang H Peskar BM Levin E Itani RM Sarfeh IJ Tarnawski SS Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healingNat Med1999 514181423

    Not in our library10.1038/70995

  130. 130.

    Tarnawski AS Jones MK Inhibition of angiogenesis by NSAIDs: molecular mechanisms and clinical implicationsJ Mol Med2003 81627636

    Not in our library10.1007/s00109-003-0479-y

  131. 131.

    Boonmasawai S Akarasereenont P Techatraisak K Thaworn A Chotewuttakorn S Palo T Effects of selective COX inhibitors and classical NSAIDs on endothelial cell proliferation and migration induced by human cholangiocarcinoma cell cultureJ Med Assoc Thai2009 9215081515

    Not in our library

  132. 132.

    Alkam T Nitta A Mizoguchi H Saito K Seshima M Itoh A Yamada K Nabeshima T Restraining tumor necrosis factor-alpha by thalidomide prevents the amyloid beta-induced impairment of recognition and memory in miceBeh Brain Res2008 189100106

    Not in our library10.1016/j.bbr.2007.12.014

  133. 133.

    Ryu JK McLarnon JG Thalidomide inhibition of perturbed vasculature and glial-derived tumor necrosis factor-alpha in an animal model of inflamed Alzheimer's disease brainNeurobiol Dis2008 29254266

    Not in our library10.1016/j.nbd.2007.08.019

  134. 134.

    Araύjo FA Rocha MA Mendes JB Andrade SP Atorvastatin inhibits inflammatory angiogenesis in mice through down regulation of VEGF, TNF-alpha and TGF-beta1Biomed Pharmacother2010 642934

    Not in our library10.1016/j.biopha.2009.03.003

  135. 135.

    Hata Y Miura M Asato R Kita T Oba K Kawahara S Arita R Kohno R Nakao S Ishibashi T Antiangiogenic mechanisms of simvastatin in retinal endothelial cellsGraefes Arch Clin Exp Ophthalmol2010 248667673

    Not in our library10.1007/s00417-009-1282-4

  136. 136.

    Wang Q Yan J Chen X Li J Yang Y Weng J Deng C Yenari MA Statins: multiple neuroprotective mechanisms in neurodegenerative diseasesExp Neurol2010 in press

    Not in our library10.1016/j.expneurol.2010.04.006

  137. 137.

    Gimbrone MA Jr Vascular endothelium, hemodynamic forces and atherogenesisAm J Pathol1999 15515

    Not in our library10.1016/s0002-9440(10)65090-0

  138. 138.

    Libby P Ridker PM Hansson GK Leducq Transatlantic Network on AtherothrombosisInflammation in atherosclerosis: from pathophysiology to practiceJ Am Coll Cardiol2009 5421292138

    Not in our library10.1016/j.jacc.2009.09.009

  139. 139.

    Gimbrone MA Jr Endothelial dysfunction, biomechanical forces and the pathobiology of atherosclerosisTrans Am Clin Climatol Assoc2010 121115127

    Not in our library

  140. 140.

    Bauersachs J Widder JD Endothelial dysfunction in heart failurePharm Reports2008 60119126

    Not in our library

  141. 141.

    Pober JS Min W Bradley JR Mechanisms of endothelial dysfunction, injury and deathAnnu Rev Pathol2009 47195

    Not in our library10.1146/annurev.pathol.4.110807.092155

  142. 142.

    Andjelkovic AV Pachter JS Central nervous system endothelium in neuroinflammatory, neuroinfectious, and neurodegenerative diseaseJ Neurosci Res1998 51423430

    Not in our library10.1002/(sici)1097-4547(19980215)51:4<423::aid-jnr2>3.0.co;2-e

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    Faraci FM Lentz SR Hyperhomocysteinemia, oxidative stress, and cerebral vascular dysfunctionStroke2004 35345347

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    Tsopanoglou NE Andriopoulou P Maragoudakis ME On the mechanism of thrombin-induced angiogenesis: involvement of alphavbeta3-integrinAm J Physiol2002 283C1501C1510

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    Turgeon VL Milligan CE Houenou LJ Activation of the protease-activated thrombin receptor (PAR)-1 induces motoneuron degeneration in the developing avian embryoJ Neuropathol Exp1999 58499504

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    Festoff BW D'Andrea MR Citron BA Salcedo RM Smirnova IV Andrade-Gordon P Motor neuron cell death in wobbler mutant mice follows overexpression of the G-protein coupled, protease-activated receptor for thrombinMol Med2000 6410429

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    Lee da Y Park KW Jin BK Thrombin induces neurodegeneration and microglial activation in the cortex in vivo and in vitro: proteolytic and non-proteolytic actionsBiochem Biophys Res Commun2006 346727738

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    Luo W Wang Y Reiser G Protease-activated receptors in the brain: receptor expression, activation, and functions in neurodegenerationBrain Res Rev2007 56331345

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    Choi MS Kim YE Lee WJ Choi JW Park GH Kim SD Jeon SJ Go HS Shin SM Kim WK Shin Cy Ko KH Activation of protease-activated receptor1 mediates induction of matrix metalloproteinase-9 by thrombin in rat primary astrocytesBrain Res Bull2008 76368375

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    Not in our library10.1212/01.wnl.0000264502.92649.ab

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    Not in our library10.1038/nrn2336

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    Not in our library10.1007/s00401-009-0522-3

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    Igarashi K Murai H Asaka J Proteolytic processing of amyloid beta protein precursor (APP) by thrombinBiochem Biophys Res1992 18510001004

    Not in our library10.1016/0006-291x(92)91726-7

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    Not in our library

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