Altered blood-brain-barrier function in Alzheimer's disease?

Mattila, Kari M.; Pirttilä, Tuula; Blennow, Kaj; Wallin, Anders; Vitanen, M.; Frey, H.

doi:10.1111/j.1600-0404.1994.tb01660.x

Cited by 59 publications

(30 citation statements)

References 38 publications

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“…All of the markers have previously been implicated in AD pathogenesis and/or similar or related pathologic processes and/or have been found to be altered in AD (Elovaara et al 1985, Johnson et al 1992, Mattila et al 1994, Davidsson et al 1999, Davidsson et al 2002, Hansson et al 2004, Castano et al 2006, Jung et al 2008). In particular, ApoA1 has been intensively studied with respect to a possible pathogenic role in AD, suggesting that its differential presence in the CSF may have mechanistic implications.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we have further tested, using ELISA methods, the differential presence of these proteins in CSF samples from individual subjects and evaluated their performance as diagnostic markers for neuropathologically-confirmed AD as compared with NADD and ND subjects. Four other markers, α-1 acid glycoprotein (A1GP), haptoglobin (HPTG), zinc α-2 glycoprotein (Z2GP) and apolipoprotein E (ApoE), were selected for evaluation on the basis of a literature review (Elovaara et al 1985, Johnson et al 1992, Mattila et al 1994, Davidsson et al 1999, Davidsson et al 2002, Puchades et al 2003, Hansson et al 2004, Jung et al 2008). Additionally, we measured the CSF concentrations of Aβ1–40, Aβ1–42, total tau protein (t-tau) and phosphorylated tau protein (p-tau) in the same subjects as these have been previously identified as the most useful diagnostic marker proteins (Galasko et al 1998, Montine et al 2001, Sjogren et al 2001, Clark et al 2003, Maddalena et al 2003, Engelborghs et al 2008).…”

Section: Introductionmentioning

confidence: 99%

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Proteomics-derived cerebrospinal fluid markers of autopsy-confirmed Alzheimer’s disease

Roher¹,

Maarouf²,

Sue

et al. 2009

Biomarkers

102

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The diagnostic performance of several candidate cerebrospinal fluid (CSF) protein biomarkers of neuropathologically-confirmed Alzheimer’s disease (AD), non-demented (ND) elderly controls and non-AD dementias (NADD) was assessed. Candidate markers were selected on the basis of initial 2-dimensional gel electrophoresis studies or by literature review. Markers selected by the former method included apolipoprotein A-1 (ApoA1), hemopexin (HPX), transthyretin (TTR) and pigment epithelium-derived factor (PEDF) while markers identified from the literature included Aβ1–40, Aβ1–42, total tau, phosphorylated tau, α-1 acid glycoprotein (A1GP), haptoglobin, zinc α-2 glycoprotein (Z2GP) and apolipoprotein E (ApoE). Ventricular CSF concentrations of the markers were measured by ELISA. The concentrations of Aβ1–42, ApoA1, A1GP, ApoE, HPX and Z2GP differed significantly among AD, ND and NADD subjects. Logistic regression analysis for the diagnostic discrimination of AD from ND found that Aβ1–42, ApoA1 and HPX each had significant and independent associations with diagnosis. The CSF concentrations of these three markers distinguished AD from ND subjects with 84% sensitivity and 72% specificity, with 78% of subjects correctly classified. By comparison, using Aβ1–42 alone gave 79% sensitivity and 61% specificity, with 68% of subjects correctly classified. For the diagnostic discrimination of AD from NADD, only the concentration of Aβ1–42 was significantly related to diagnosis, with a sensitivity of 58%, specificity of 86% and 86% correctly classified. The results indicate that for the discrimination of AD from ND control subjects, measurement of a set of markers including Aβ1–42, ApoA1 and HPX improved diagnostic performance over that obtained by measurement of Aβ1–42 alone. For the discrimination of AD from NADD subjects, measurement of Aβ1–42 alone was superior.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proteomics-derived cerebrospinal fluid markers of autopsy-confirmed Alzheimer’s disease

Roher¹,

Maarouf²,

Sue

et al. 2009

Biomarkers

102

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“…Increased free Hb in human serum has recently been found associated with AD relative to controls [109]. This and several other reports indicate that haptoglobin is increased in AD plasma and CSF [44,62,107]. This may represent an attempt to adjust the homeostatic level in response to chronic hemolysis, although inflammation, which is also associated with AD, can lead to increased haptoglobin levels [50].…”

Section: Discussionmentioning

confidence: 71%

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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“…The brain is an immunologically privileged site because of blood-brain barrier (BBB), which blocks the entry of macromolecules into the brain, such as immunoglobulins (Ig) and cells, including the immunocompetent ones, thus protecting and isolating brain from organism's immune reaction. If the integrity of BBB is destroyed by microvascular injury or inflammation, increasing amounts of immunocompetent macromolecules and cells including T and B cells will pass BBB into the brain, especially hippocampus, and then cause increased expression of major histocompatibility complex (MHC) I and II in endothelial cells and glia cells, thus triggering subsequent autoimmune response (Mattila et al 1994;Sardi et al 2011). Under physiological conditions, synaptic connected proteins are not recognized by immune system cells.…”

Section: Discussionmentioning

confidence: 99%

Global Gene Expression Profile of the Hippocampus in a Rat Model of Vascular Dementia

Feng

et al. 2015

Tohoku J. Exp. Med.

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Vascular dementia (VD) has been one of the most serious public health problems worldwide. It is well known that cerebral hypoperfusion is the key pathophysiological basis of VD, but it remains unclear how global genes in hippocampus respond to cerebral ischemia-reperfusion. In this study, we aimed to reveal the global gene expression profile in the hippocampus of VD using a rat model. VD was induced by repeated occlusion of common carotid arteries followed by reperfusion. The rats with VD were characterized by deficit of memory and cognitive function and by the histopathological changes in the hippocampus, such as a reduction in the number and the size of neurons accompanied by an increase in intercellular space. Microarray analysis of global genes displayed up-regulation of 7 probesets with genes with fold change more than 1.5 (P < 0.05) and down-regulation of 13 probesets with genes with fold change less than 0.667 (P < 0.05) in the hippocampus. Gene Ontology (GO) and pathway analysis showed that the up-regulated genes are mainly involved in oxygen binding and transport, autoimmune response and inflammation, and that the down-regulated genes are related to glucose metabolism, autoimmune response and inflammation, and other biological process, related to memory and cognitive function. Thus, the abnormally expressed genes are closely related to oxygen transport, glucose metabolism, and autoimmune response. The current findings display global gene expression profile of the hippocampus in a rat model of VD, providing new insights into the molecular pathogenesis of VD.

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Altered blood-brain-barrier function in Alzheimer's disease?

Cited by 59 publications

References 38 publications

Proteomics-derived cerebrospinal fluid markers of autopsy-confirmed Alzheimer’s disease

Proteomics-derived cerebrospinal fluid markers of autopsy-confirmed Alzheimer’s disease

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

Global Gene Expression Profile of the Hippocampus in a Rat Model of Vascular Dementia

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