Soluble Alzheimers β-amyloid constricts the cerebral vasculature in vivo

Suo, Zhiming; Humphrey, James; Kundtz, Amy; Sethi, Faisil; Placzek, Andon N.; Crawford, Fiona; Mullan, Michael

doi:10.1016/s0304-3940(98)00814-3

Cited by 108 publications

(94 citation statements)

References 17 publications

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“…The above observations are consistent with some of the morphological and inflammatory changes associated with the vasculature in AD [20][21][22]80,95]. This may be, in part mediated by Aβ interactions with RBCs and free Hb, and, in particular, with metHb A.…”

Section: Discussionsupporting

confidence: 83%

See 1 more Smart Citation

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

Perry

Gearhart

Wiener

et al. 2008

Neurobiology of Aging

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From a normal human brain phage display library screen we identified the gamma (A)-globin chain of fetal hemoglobin (Hb F) as a protein that bound strongly to Aβ1-42. We showed the oxidized form 1 These authors are co-corresponding authors for all stages of refereeing and publication and contributed equally to this work. Rodney T. Perry; Rm. 210H, 1665 University Blvd.; University of Alabama at Birmingham, Birmingham, USA; Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Disclosure Statement:I so state for myself and on behalf of the other authors on the manuscript, Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease, that we have no conflicts and sources of funding that influence the results of this paper, the data is not published or submitted elsewhere, and that appropriate approval and procedures were used concerning human subjects. I also verify that all authors on this manuscript have reviewed the contents of the manuscript, approve of its contents, and validate the accuracy of the data. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript of adult Hb (metHb A) binds with greater affinity to Aβ1-42 than metHb F. MetHb is more toxic than oxyhemoglobin because it loses its heme group more readily. Free Hb and heme readily damage vascular endothelial cells similar to Alzheimer's disease (AD) vascular pathology. The XmnI polymorphism (C→T) at −158 of the gamma (G)-globin promoter region can contribute to increased Hb F expression. Using family-based association testing, we found a significant protective association of this polymorphism in the NIMH sibling dataset (n=489) in families, with at least two affected and one unaffected sibling (p=0.006), with an age of onset >50 years (p=0.010) and >65 years (p=0.013), and families not homozygous for the APOE4 allele (p=0.041). We hypothesize that Hb F may be less toxic than adult Hb in its interaction with Aβ and may protect against the development of AD.

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Section: Discussionsupporting

confidence: 83%

“…Interestingly, vascular changes, including hypoperfusion, appear to precede evidence of neuronal injury [21]. Morphological and inflammatory changes are consistently observed in the brain vasculature in AD [21,95].…”

Section: Aβ and Cerebral Amyloid Angiopathymentioning

confidence: 99%

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

Perry

Gearhart

Wiener

et al. 2008

Neurobiology of Aging

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“…Aβ has been shown to have a constrictive effect on the cerebral vasculature [10], and interestingly, to be neuroprotective at low physiological concentrations [11]. For this reason Aβ has been suggested to have a dual damage response role in the brain, by sealing the vasculature reducing brain oxygen requirement and combating oxidative stress [12].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

“…Aβ has been reported to exhibit a constrictive effect on cerebral vessels [10] but it is unclear whether Aβ levels are increased in the AD retina. Plaques and tangles have not been found in the human retina although Aβ has been isolated in aged human retinas [132].…”

Section: (Figure 4)mentioning

confidence: 99%

Ocular Biomarkers for Early Detection of Alzheimer's Disease

Frost

Martins

Kanagasingam

2010

JAD

100

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Alzheimer's disease (AD) is the most common form of dementia and is characterized clinically by a progressive decline in memory, learning and executive function and neuropathologically by the presence of cerebral amyloid deposits. Despite a century of research, there is still no cure or conclusive pre-mortem diagnosis for the disease. A number of symptom-modifying drugs for AD have been developed, but their efficacy is minimal and short-lived. AD cognitive symptoms arise only after significant, irreversible neural deterioration has occurred, hence there is an urgent need to detect AD early, before the onset of cognitive symptoms. An accurate, early diagnostic test for AD would enable current and future treatments to be more effective, as well as contribute to the development of new treatments.While most AD related pathology occurs in the brain, the disease has also been reported to affect the eye, which is more accessible for imaging than the brain. AD-related proteins exist in the normal human eye and may produce ocular pathology in AD. There is some homology between the retinal and cerebral vasculatures and the retina also contains nerve cells and fibers that form a sensory extension of the brain. The eye is the only place in the body where vasculature or neural tissue is available for non-invasive optical imaging. This article presents a review of current literature on ocular morphology in AD and discusses the potential for an ocular based screening test for AD.

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“…In these studies animals were not observed to develop brain microinfarcts, hemorrhage, white matter changes, or high blood pressure, but CBF, when measured, was reduced to 25% to 33% of baseline. 158,159 Reduction of CBF can also be obtained with the intravenous administration of freshly solubilized A␤ 1-40 in mice 160,161 but not with the use of the reverse peptide A␤ 40-1 . 161 In addition to the cerebral hypoperfusion observed in these rodents, regional vasoconstriction and increased vascular resistance are also seen, particularly in brain cortex.…”

mentioning

confidence: 99%

Alzheimer Disease as a Vascular Disorder

Torre

2002

Stroke

777

491

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Background-The main stumbling block in the clinical management and in the search for a cure of Alzheimer disease (AD) is that the cause of this disorder has remained uncertain until now. Summary of Review-Evidence that sporadic (nongenetic) AD is primarily a vascular rather than a neurodegenerative disorder is reviewed. This conclusion is based on the following evidence: (1) epidemiological studies showing that practically all risk factors for AD reported thus far have a vascular component that reduces cerebral perfusion; (2) risk factor association between AD and vascular dementia (VaD); (3) improvement of cerebral perfusion obtained from most pharmacotherapy used to reduce the symptoms or progression of AD; (4) detection of regional cerebral hypoperfusion with the use of neuroimaging techniques to preclinically identify AD candidates; (5) presence of regional brain microvascular abnormalities before cognitive and neurodegenerative changes; (6) common overlap of clinical AD and VaD cognitive symptoms; (7) similarity of cerebrovascular lesions present in most AD and VaD patients; (8) presence of cerebral hypoperfusion preceding hypometabolism, cognitive decline, and neurodegeneration in AD; and (9) confirmation of the heterogeneous and multifactorial nature of AD, likely resulting from the diverse presence of vascular risk factors or indicators of vascular disease. Conclusions-Since the value of scientific evidence generally revolves around probability and chance, it is concluded that the data presented here pose a powerful argument in support of the proposal that AD should be classified as a vascular disorder. According to elementary statistics, the probability or chance that all these findings are due to an indirect pathological effect or to coincidental circumstances related to the disease process of AD seems highly unlikely. The collective data presented in this review strongly support the concept that sporadic AD is a vascular disorder. It is recommended that current clinical management of patients, treatment targets, research designs, and disease prevention efforts need to be critically reassessed and placed in perspective in light of these important findings. Key Words: Alzheimer disease Ⅲ dementia Ⅲ microcirculation Ⅲ risk factors Ⅲ vascular disorders A lzheimer disease (AD) is an insidious disorder that progressively ravages the brain, destroying its memory, intellect, and dignity in the process. The main stumbling block in the clinical management and in the search for a cure of AD is that the cause of this disorder has remained uncertain until now. For more than 30 years, AD has been classified and managed as a neurodegenerative disorder, 1,2 following a report by Roth in 1955 3 that suggested that dementia should be classified into 2 distinct disorders according to the variable mental changes caused by each: vascular dementia (VaD), caused by vascular lesions, and AD, resulting from a neurodegenerative process.Most investigators in the field have supported Roth's notion that dementing processes will d...

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Soluble Alzheimers β-amyloid constricts the cerebral vasculature in vivo

Cited by 108 publications

References 17 publications

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

Hemoglobin binding to Aβ and HBG2 SNP association suggest a role in Alzheimer's disease

Ocular Biomarkers for Early Detection of Alzheimer's Disease

Alzheimer Disease as a Vascular Disorder

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