Physiological levels of<i>β</i>-amyloid induce cerebral vessel dysfunction and reduce endothelial nitric oxide production

Price, J. M.; Chi, Xuedong; Hellermann, Gary; Sutton, E. T.

doi:10.1179/016164101101198758

Cited by 76 publications

(55 citation statements)

References 38 publications

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“…Similar activities have been reported for Ab, which inhibits cerebral blood flow, counteracts acetylcholine activity on blood vessels, inhibits angiogenesis and is cytotoxic for endothelial cells. 51,52 The effect of Ab on cell surface-associated ATP synthase complex in endothelial cells may account for the cerebral amyloid angiopathy aspect of Alzheimer's disease pathology.…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

et al. 2007

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Amyloid precursor protein (APP) and amyloid b-peptide (Ab) have been implicated in a variety of physiological and pathological processes underlying nervous system functions. APP shares many features with adhesion molecules in that it is involved in neurite outgrowth, neuronal survival and synaptic plasticity. It is, thus, of interest to identify binding partners of APP that influence its functions. Using biochemical cross-linking techniques we have identified ATP synthase subunit a as a binding partner of the extracellular domain of APP and Ab. APP and ATP synthase colocalize at the cell surface of cultured hippocampal neurons and astrocytes. ATP synthase subunit a reaches the cell surface via the secretory pathway and is N-glycosylated during this process. Transfection of APP-deficient neuroblastoma cells with APP results in increased surface localization of ATP synthase subunit a. The extracellular domain of APP and Ab partially inhibit the extracellular generation of ATP by the ATP synthase complex. Interestingly, the binding sequence of APP and Ab is similar in structure to the ATP synthase-binding sequence of the inhibitor of F1 (IF 1 ), a naturally occurring inhibitor of the ATP synthase complex in mitochondria. In hippocampal slices, Ab and IF 1 similarly impair both short-and long-term potentiation via a mechanism that could be suppressed by blockade of GABAergic transmission. These observations indicate that APP and Ab regulate extracellular ATP levels in the brain, thus suggesting a novel mechanism in Ab-mediated Alzheimer's disease pathology.

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Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

et al. 2007

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“…Ex vivo studies with isolated cerebral arterioles show that synthetic Aβ 40 (and to a lesser degree Aβ 42 ) induces direct vessel constriction, enhanced response to vasoconstrictors, and reduced response to vasodilators (14)(15)(16)(17)(18)(19)(20)(21)(22).…”

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confidence: 99%

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

Han

Zhou

Johnson

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

103

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Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid β peptide (Aβ) within walls of cerebral arteries and is an important cause of intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in elderly patients with and without Alzheimer's Disease (AD). NADPH oxidase-derived oxidative stress plays a key role in soluble Aβ-induced vessel dysfunction, but the mechanisms by which insoluble Aβ in the form of CAA causes cerebrovascular (CV) dysfunction are not clear. Here, we demonstrate evidence that reactive oxygen species (ROS) and, in particular, NADPH oxidase-derived ROS are a key mediator of CAA-induced CV deficits. First, the NADPH oxidase inhibitor, apocynin, and the nonspecific ROS scavenger, tempol, are shown to reduce oxidative stress and improve CV reactivity in aged Tg2576 mice. Second, the observed improvement in CV function is attributed both to a reduction in CAA formation and a decrease in CAA-induced vasomotor impairment. Third, anti-ROS therapy attenuates CAA-related microhemorrhage. A potential mechanism by which ROS contribute to CAA pathogenesis is also identified because apocynin substantially reduces expression levels of ApoE-a factor known to promote CAA formation. In total, these data indicate that ROS are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage. Thus, ROS and, in particular, NADPH oxidase-derived ROS are a promising therapeutic target for patients with CAA and AD.Alzheimer's disease | cerebral amyloid angiopathy | reactive oxygen species | NADPH oxidase | vasomotor dysfunction

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“…These alterations could depend on the damaging effect of circulating Ap and ROS. The Ap peptide, generated from the amyloid p precursor protein (APP), is capable of interacting with endothelial cells to produce superoxide radicals, and inhibits NO generation or action (10,12). The endothelium also represents a major target of oxidative stress, which plays a relevant role in the pathophysiology of several vascular disorders (25).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that Ap may damage the vascular endothelium. In particular, it has previously been suggested that a slight increase in Ap above its physiological levels in the circulation, as found in the early stages of AD, can induce a decrease in NO production that may lead to vasoconstriction and ischemia, while high concentrations ofAp stimulate endothelial cell death (12).…”

mentioning

confidence: 99%

Effects of Plasma from Patients Affected by Mild Cognitive Impairment and Alzheimer's Disease on Cultured Endothelial Cells

et al. 2013

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There is accumulating evidence that Alzheimer's disease (AD) can have vascular contribution. In particular, endothelial dysfunction may impair nitric oxide (NO) production and cause cerebral hypoperfusion. Blood flow impairment can be provoked also by an increased production of reactive oxygen species (ROS). The present study was performed in order to investigate the effect of plasma from subjects affected by AD and mild cognitive impairment (MCI) on human aortic endothelial cells (HAECs) in vitro, since endothelial dysfunction has been suggested to be an early event in patients affected by AD. Plasma samples were obtained from 27 AD patients, 15 MCI subjects, and 19 ageand sex-matched healthy subjects. After a short incubation period the following parameters were evaluated: NO release, superoxide dismutase (SOD) and Na+fK+-ATPase activities, membrane fluidity, and thiobarbituric acid-reactive substance (TBARS) production. Exposure to MCI plasma provoked a decrease in NO release, more pronounced in the presence of AD plasma. Our data on SOD and Na+IK+-ATPase activities showed a similar trend, since the lowest values were recorded after incubation with AD plasma. Endothelial membrane fluidity was deeply affected by the exposure to MCI plasma, and even more following incubation with AD plasma. Finally, enhanced TBARS production after incubation with MCI and AD plasma was observed. In conclusion, our results showed that MCI and AD plasma affects endothelial cells, thus highlighting the need for early treatment aimed at protecting the endothelium.Alzheimer's disease (AD) represents the most common cause of dementia in the older population. It is characterized by the presence of senile plaques distributed throughout the cerebral cortex, as well as intraneuronal neurofibrillary tangles, although it is known to be a systemic disorder (1, 2).There is accumulating evidence that AD may have a vascular basis that involves impaired nitric oxide (NO) release, resulting in cerebral hypoperfusion (3). NO is a multifunctional free radical synthesized from L-arginine by NO synthases (NOS). Endothelial (eNOS) and neuronal (nNOS) isoforms are constitutively expressed and depend on intracellular calcium release, while inducible NOS (iNOS) is calcium independent and usually expressed in response to inflammatory cytokines and

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Physiological levels ofβ-amyloid induce cerebral vessel dysfunction and reduce endothelial nitric oxide production

Cited by 76 publications

References 38 publications

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

Amyloid precursor protein and amyloid β-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

Effects of Plasma from Patients Affected by Mild Cognitive Impairment and Alzheimer's Disease on Cultured Endothelial Cells

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