Alzheimer Disease: Iadecola C

Hachinski V, Iadecola C, Petersen RC, Breteler MM, Nyenhuis DL, Black SE, Powers WJ, DeCarli C, Merino JG, Kalaria RN, Vinters HV, Holtzman DM, Rosenberg GA, Wallin A, Dichgans M, Marler JR, Leblanc GG. · London Health Sciences Centre, University Campus, London, Ontario, Canada. · Stroke. · Pubmed #16917086 links to  free full text

Abstract: BACKGROUND AND PURPOSE: One in 3 individuals will experience a stroke, dementia or both. Moreover, twice as many individuals will have cognitive impairment short of dementia as either stroke or dementia. The commonly used stroke scales do not measure cognition, while dementia criteria focus on the late stages of cognitive impairment, and are heavily biased toward the diagnosis of Alzheimer disease. No commonly agreed standards exist for identifying and describing individuals with cognitive impairment, particularly in the early stages, and especially with cognitive impairment related to vascular factors, or vascular cognitive impairment. METHODS: The National Institute for Neurological Disorders and Stroke (NINDS) and the Canadian Stroke Network (CSN) convened researchers in clinical diagnosis, epidemiology, neuropsychology, brain imaging, neuropathology, experimental models, biomarkers, genetics, and clinical trials to recommend minimum, common, clinical and research standards for the description and study of vascular cognitive impairment. RESULTS: The results of these discussions are reported herein. CONCLUSIONS: The development of common standards represents a first step in a process of use, validation and refinement. Using the same standards will help identify individuals in the early stages of cognitive impairment, will make studies comparable, and by integrating knowledge, will accelerate the pace of progress.

Iadecola C. · No affiliation provided · Arterioscler Thromb Vasc Biol. · Pubmed #14617615 links to  free full text

This publication has no abstract.

Iadecola C, Gorelick PB. · Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA. · Stroke. · Pubmed #12574528 links to  free full text

This publication has no abstract.

Iadecola C, Park L, Capone C. · Division of Neurobiology, Weill Medical College of Cornell University, 411 East 69th Street; KB410, New York, NY 10021, USA. · Stroke. · Pubmed #19064785 links to  free full text

Abstract: Aging, Alzheimer disease, and hypertension, major determinants of cognitive dysfunction, are associated with profound alterations in the structure and function of cerebral blood vessels. These vascular alterations may impair the delivery of energy substrates and nutrients to the active brain, and impede the clearance of potentially toxic metabolic byproducts. Reactive oxygen species derived form the enzyme NADPH oxidase are key pathogenic effectors of the cerebrovascular dysregulation. The resulting alterations in the homeostasis of the cerebral microenvironment may lead to cellular dysfunction and death and to cognitive impairment. The prominent role that cerebrovascular oxidative stress plays in conditions associated with cognitive impairment suggests new therapeutic opportunities to counteract and, possibly, reverse the devastating effects of cerebrovascular dysfunction on the brain.

Girouard H, Iadecola C. · Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York, USA. · J Appl Physiol. · Pubmed #16357086 links to  free full text

Abstract: The brain is critically dependent on a continuous supply of blood to function. Therefore, the cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the energy needs of its cellular constituents. The regulation of cerebral blood flow (CBF) during brain activity involves the coordinated interaction of neurons, glia, and vascular cells. Thus, whereas neurons and glia generate the signals initiating the vasodilation, endothelial cells, pericytes, and smooth muscle cells act in concert to transduce these signals into carefully orchestrated vascular changes that lead to CBF increases focused to the activated area and temporally linked to the period of activation. Neurovascular coupling is disrupted in pathological conditions, such as hypertension, Alzheimer disease, and ischemic stroke. Consequently, CBF is no longer matched to the metabolic requirements of the tissue. This cerebrovascular dysregulation is mediated in large part by the deleterious action of reactive oxygen species on cerebral blood vessels. A major source of cerebral vascular radicals in models of hypertension and Alzheimer disease is the enzyme NADPH oxidase. These findings, collectively, highlight the importance of neurovascular coupling to the health of the normal brain and suggest a therapeutic target for improving brain function in pathologies associated with cerebrovascular dysfunction.

Iadecola C. · Division of Neurobiology, Weill Medical College of Cornell University, room KB410, 411 East 69th Street, New York, New York 10021, USA. · Nat Rev Neurosci. · Pubmed #15100718 No free full text.

This publication has no abstract.

Iadecola C. · Division of Neurobiology, Weill Medical College of Cornell University, 411 East 69th Street, New York, New York 10021, USA. · Cell Mol Neurobiol. · Pubmed #14514024 No free full text.

Abstract: 1. The amyloid B-peptide (AB) is involved in the mechanisms of Alzheimer dementia. This paper reviews experimental evidence indicating that AB exerts profound effects on the regulation of the cerebral circulation. 2. Thus, AB compromises the ability of cerebral endothelial cells to produce vascular relaxing factors, impairs the ability of cerebral blood vessels to maintain adequate flow during hypotension, and attenuates the increases in CBF evoked by enhanced brain activity. 3. Studies in transgenic mice overexpressing the amyloid precursor protein suggest that these cerebrovascular alterations disrupt the delicate balance between the brain's energy requirements and cerebral blood supply, rendering the brain more vulnerable to ischemic injury. 4. The findings support the recently emerged notion that vascular factors play a pathogenic role in the early stages of Alzheimer dementia.

Park L, Anrather J, Zhou P, Frys K, Pitstick R, Younkin S, Carlson GA, Iadecola C. · Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA. · J Neurosci. · Pubmed #15716413 links to  free full text

Abstract: Overproduction of the amyloid beta (Abeta) peptide is a key factor in the pathogenesis of Alzheimer's disease (AD), but the mechanisms of its pathogenic effects have not been defined. Patients with AD have cerebrovascular alterations attributable to the deleterious effects of Abeta on cerebral blood vessels. We report here that NADPH oxidase, the major source of free radicals in blood vessels, is responsible for the cerebrovascular dysregulation induced by Abeta. Thus, the free-radical production and the associated alterations in vasoregulation induced by Abeta are abrogated by the NADPH oxidase peptide inhibitor gp91ds-tat and are not observed in mice lacking the catalytic subunit of NADPH oxidase (gp91phox). Furthermore, oxidative stress and cerebrovascular dysfunction do not occur in transgenic mice overexpressing the amyloid precursor protein but lacking gp91phox. The mechanisms by which NADPH oxidase-derived radicals mediate the cerebrovascular dysfunction involve reduced bioavailability of nitric oxide. Thus, a gp91phox-containing NADPH oxidase is the critical link between Abeta and cerebrovascular dysfunction, which may underlie the alteration in cerebral blood flow regulation observed in AD patients.

Park L, Anrather J, Forster C, Kazama K, Carlson GA, Iadecola C. · Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, USA. · J Cereb Blood Flow Metab. · Pubmed #15091114 No free full text.

Abstract: We investigated the role of vascular oxidative stress in the mechanisms of the impairment in cerebrovascular regulation produced by the amyloid-beta peptide (Abeta). In particular, we sought to provide evidence of vascular oxidative stress in mice overexpressing the amyloid precursor protein (APP) and to determine whether the Abeta-induced attenuation in functional hyperemia is mediated by free radical overproduction. Oxidative/nitrosative stress was assessed by 3-nitrotyrosine immunoreactivity, while free radical production was determined in cerebral microvessels by hydroethidine microfluorography. To study functional hyperemia the somatosensory cortex was activated by whisker stimulation while local blood flow was monitored by laser-Doppler flowmetry. It was found that APP mice show signs of oxidative/nitrosative stress in pial and intracerebral blood vessels well before they develop oxidative stress in neurons and glia or amyloid plaques. Treatment of cerebral microvessels isolated from wild-type mice with Abeta (1 microM) increased free radical production as assessed by the hydroethidine technique. The Abeta-induced attenuation of the increase in somatosensory cortex blood flow produced by whisker stimulation was prevented by treatment with the free radical scavengers MnTBAP or tiron. These data provide evidence that in APP mice vascular oxidative stress precedes the development of parenchymal oxidative stress, and that Abeta-produced vascular reactive oxygen species are involved in the attendant attenuation in functional hyperemia. Thus, vascular oxidative stress is an early event in the course of the brain dysfunction produced by APP overexpression and Abeta, and, as such, could be the target of early therapeutic interventions based on antioxidants.

Niwa K, Kazama K, Younkin L, Younkin SG, Carlson GA, Iadecola C. · Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455, USA. · Am J Physiol Heart Circ Physiol. · Pubmed #12063304 links to  free full text

Abstract: The amyloid-beta (A beta) peptide, which is derived from the amyloid precursor protein (APP), is involved in the pathogenesis of Alzheimer's dementia and impairs endothelium-dependent vasodilation in cerebral vessels. We investigated whether cerebrovascular autoregulation, i.e., the ability of the cerebral circulation to maintain flow in the face of changes in mean arterial pressure (MAP), is impaired in transgenic mice that overexpress APP and A beta. Neocortical cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry in anesthetized APP(+) and APP(-) mice. MAP was elevated by intravenous infusion of phenylephrine and reduced by controlled exsanguination. In APP(-) mice, autoregulation was preserved. However, in APP(+) mice, autoregulation was markedly disrupted. The magnitude of the disruption was linearly related to brain A beta concentration. The failure of autoregulation was paralleled by impairment of the CBF response to endothelium-dependent vasodilators. Thus A beta disrupts a critical homeostatic mechanism of the cerebral circulation and renders CBF highly dependent on MAP. The resulting alterations in cerebral perfusion may play a role in the brain dysfunction and periventricular white-matter changes associated with Alzheimer's dementia.

Niwa K, Kazama K, Younkin SG, Carlson GA, Iadecola C. · Center for Clinical and Molecular Neurobiology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA. · Neurobiol Dis. · Pubmed #11848685 No free full text.

Abstract: We have used quantitative autoradiographic techniques to study the relationship between cerebral blood flow (CBF) and glucose utilization (CGU) in two lines of transgenic mice overexpressing Swedish mutant amyloid precursor protein (APP) and APP-derived Abeta peptides. Mice were studied at an age when there are no amyloid plaques. In the 2123 line, CBF was reduced only in telencephalic regions with no corresponding decrease in CGU. In 2576 transgenics, a line with higher levels of Abeta peptide, both CBF and CGU were reduced throughout the brain. The data indicate that Abeta induces alterations in resting CBF that are either associated with or independent of alterations in CGU and that occur in the absence of amyloid deposition in neuropil of blood vessels. These observations support the hypothesis that cerebrovascular and metabolic abnormalities are early events in the pathogenesis of Alzheimer's disease.

Niwa K, Porter VA, Kazama K, Cornfield D, Carlson GA, Iadecola C. · Center for Clinical and Molecular Neurobiology, Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA. · Am J Physiol Heart Circ Physiol. · Pubmed #11709407 links to  free full text

Abstract: Amyloid-beta (A beta)-peptides are involved in the pathophysiology of Alzheimer's dementia. We studied the effects of A beta on selected constrictor responses of cerebral circulation. Mice were anesthetized (by using urethane-chloralose) and equipped with a cranial window. Arterial pressure and blood gases were monitored and controlled. Cerebral blood flow (CBF) was monitored by a laser Doppler probe. Topical superfusion with A beta 1-40 (0.1-10 microM), but not with the reverse peptide A beta 40-1, reduced resting CBF (-29 +/- 4% at 5 microM; P < 0.05) and augmented the reduction in CBF produced by the thromboxane analog U-46619 (+45 +/- 3% at 5 microM; P < 0.05). A beta 1-40 or A beta 1-42 did not affect the reduction in CBF produced by hypocapnia. The reduction in resting CBF and the enhancement of vasoconstriction were reversed by treatment with the free radical scavengers superoxide dismutase or manganic(I-II)meso-tetrakis(4-benzoic acid)porphyrin. Substitution of the methionine residue in position 35 with norleucine, a mutation that abolishes the ability of A beta to produce free radicals, abolished its vascular effects. Nanomolar concentrations of A beta 1-40 constricted isolated pressurized middle cerebral artery segments with intrinsic tone (-16 +/- 3% at 100 nM; P < 0.05). We conclude that A beta acts directly on cerebral arteries to produce vasoconstriction and to enhance selected constrictor responses. The evidence supports the idea that A beta-induced production of reactive oxygen species plays a role in this effect. The vascular actions of A beta may contribute to the deleterious effects resulting from accumulation of this peptide in Alzheimer's dementia.

Iadecola C. · No affiliation provided · Nat Med. · Pubmed #16145570 No free full text.

This publication has no abstract.