Increased levels of hemoglobin-derived and other peptides in Alzheimer's disease cerebellum

Slemmon, J. Randall; Hughes, Carmel; Ga, Campbell; Flood, DG

doi:10.1523/jneurosci.14-04-02225.1994

Cited by 90 publications

(62 citation statements)

References 35 publications

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“…Increased levels of haemoglobin-derived peptides have been reported in the brain tissue of Alzhemier patients [15]. Of several hundred peaks analysed by RP-HPLC, 15 peaks were elevated in Alzheimer's patients.…”

Section: Resultsmentioning

confidence: 99%

The recognition of haemoglobin by antibodies raised for the immunoassay of β‐amyloid

et al. 1997

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Canine and porcine cerebrospinal fluid (CSF) were fractionated by size exclusion chromatography and analysed by a luminescence enzyme linked immunosorbent assay (ELISA) configured to detect P-amyloid. A peak of activity was observed in the CSF consistent with the molecular weight of P-amyloid. When CSF contaminated with blood was analysed an additional peak of immunoreactivity at a higher molecular weight was observed. The peak of activity was found to be derived from cross-reactivity of the immunoglobulins employed in the ELISA with haemoglobin. These findings are discussed with reference to primary and structural sequence homology between P-amyloid and haemoglobin from a number of species, the known properties of P-amyloid and recent clinical reports.© 1997 Federation of European Biochemical Societies.

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Section: Resultsmentioning

confidence: 99%

The recognition of haemoglobin by antibodies raised for the immunoassay of β‐amyloid

et al. 1997

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“…Peptides related or derived from hemoglobin are found in increased concentration in cerebellums from AD patients. 34 These peptides may have arisen from an increased leakage of blood in AD as suggested by the work of De Reuck 35 or by decreased clearance of these peptides by the AD brain. Prothrombin is not produced by the normal brain but shows increased levels in AD brains consistent with leakage across a disrupted BBB.…”

Section: Histologic Studiesmentioning

confidence: 99%

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

Erickson

Banks

2013

J Cereb Blood Flow Metab

476

363

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The blood-brain barrier (BBB) plays critical roles in the maintenance of central nervous system (CNS) homeostasis. Dysfunction of the BBB occurs in a number of CNS diseases, including Alzheimer's disease (AD). A prevailing hypothesis in the AD field is the amyloid cascade hypothesis that states that amyloid-b (Ab) deposition in the CNS initiates a cascade of molecular events that cause neurodegeneration, leading to AD onset and progression. In this review, the participation of the BBB in the amyloid cascade and in other mechanisms of AD neurodegeneration will be discussed. We will specifically focus on three aspects of BBB dysfunction: disruption, perturbation of transporters, and secretion of neurotoxic substances by the BBB. We will also discuss the interaction of the BBB with components of the neurovascular unit in relation to AD and the potential contribution of AD risk factors to aspects of BBB dysfunction. From the results discussed herein, we conclude that BBB dysfunction contributes to AD through a number of mechanisms that could be initiated in the presence or absence of Ab pathology. Keywords: Alzheimer's disease; blood-brain barrier; cerebrospinal fluid; diabetes; inflammation; neurovascular unit INTRODUCTION Alzheimer's disease (AD) is the most common type of dementia, and affects B36 million individuals worldwide (http://www.alz. co.uk/research/world-report). The majority of individuals afflicted with AD initially present with symptoms of memory loss and cognitive impairment late in life (Z65 years old). These symptoms increase in severity as AD progresses, often become so debilitating that institutionalization is necessary, and are eventually fatal. Therefore, AD is a disease with tremendous socioeconomic cost. Because of the growing aged population and lack of treatments that can prevent or slow disease progression, future AD prevalence is expected to increase to an extent that it may threaten the sustainability of healthcare systems worldwide. This necessitates a global effort to better understand AD, with the goal of developing treatments that can prevent or slow AD progression. Journal of Cerebral BloodMuch of the focus in AD research has been on amyloid-b peptide (Ab) and tau, which are the protein constituents of the hallmark senile plaques and neurofibrillary tangles that pathologically define AD. The amyloid cascade hypothesis, initially proposed by Hardy and Higgins in 1992, 1 updated by Hardy and Selkoe in 2002, 2 and still a prevalent focus of AD research today, states that deposition of Ab in the brain is the initiating event in AD. Although the hypothesis remains generally accepted, it is also increasingly evident that Ab plays a complex, multifaceted role in AD progression. In rare, familial forms of AD, mutations in the Ab precursor protein (APP) or in presenilin proteins, the enzymes that cleave Ab from APP, cause increased Ab deposition. In the remainder of AD cases, it is thought that Ab deposition results from deficient clearance. 2 Multiple routes of clearance have been elucidat...

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“…Hb, Hb derived peptides, and Hb mRNA levels have been reported to be increased in AD brains relative to the brains of non-demented control subjects [17,75,85,91,105]. Brain Hb levels in AD were highest in the hippocampus and parietal gray and white matter and lowest in the cerebellum, and there was co-localization of Hb with senile plaques and CAA [105].…”

Section: Hb and Heme In Ad Brains And Its Vasculaturementioning

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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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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Increased levels of hemoglobin-derived and other peptides in Alzheimer's disease cerebellum

Cited by 90 publications

References 35 publications

The recognition of haemoglobin by antibodies raised for the immunoassay of β‐amyloid

The recognition of haemoglobin by antibodies raised for the immunoassay of β‐amyloid

Blood–Brain Barrier Dysfunction as a Cause and Consequence of Alzheimer's Disease

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

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