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Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1 ΔE9 Mice.

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Title: Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1 ΔE9 Mice.
Authors: Lefterov, Iliya1 iliyal@pitt.edu, Fitz, Nicholas F.1, Cronican, Andrea A.1, Fogg, Allison1, Lefterov, Preslav1, Kodali, Ravindra2,3, Wetzel, Ronald2,3, Koldamova, Radosveta1 radak@pitt.edu
Source: Journal of Biological Chemistry. 11/19/2010, Vol. 285 Issue 47, p36945-36957. 13p.
Subjects: Apolipoproteins, Protein deficiency, Cerebral amyloid angiopathy, Animal models of Alzheimer's disease, Cerebral circulation, Amyloid beta-protein precursor, Oligomers
Abstract: A hallmark of Alzheimer disease (AD) is the deposition of amyloid β (Aβ) in brain parenchyma and cerebral blood vessels, accompanied by cognitive decline. Previously, we showed that human apolipoprotein A-I (apoA-I) decreases Aβ40 aggregation and toxicity. Here we demonstrate that apoA-I in lipidated or non-lipidated form prevents the formation of high molecular weight aggregates of Aβ42 and decreases Aβ42 toxicity in primary brain cells. To determine the effects of apoA-I on AD phenotype in vivo, we crossed APP/PS1ΔE9 to apoA-IKO mice. Using a Morris water maze, we demonstrate that the deletion of mouse Apoa-I exacerbates memory deficits in APP/PS1ΔE9 mice. Further characterization of APP/PS1ΔE9/apoA-IKO mice showed that apoA-I deficiency did not affect amyloid precursor protein processing, soluble Aβ oligomer levels, Aβ plaque load, or levels of insoluble Aβ in brain parenchyma. To examine the effect of Apoa-I deletion on cerebral amyloid angiopathy, we measured insoluble Aβ isolated from cerebral blood vessels. Our data show that in APP/PS1ΔE9/apoA-IKO mice, insoluble Aβ40 is increased more than 10-fold, and Aβ42 is increased 1.5-fold. The increased levels of deposited amyloid in the vessels of cortices and hippocampi of APP/PS1ΔE9/apoA-IKO mice, measured by X-34 staining, confirmed the results. Finally, we demonstrate that lipidated and non-lipidated apoA-I significantly decreased Aβ toxicity against brain vascular smooth muscle cells. We conclude that lack of apoA-I aggravates the memory deficits in APP/PS1ΔE9 mice in parallel to significantly increased cerebral amyloid angiopathy. [ABSTRACT FROM AUTHOR]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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  Data: Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1 ΔE9 Mice.
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  Data: <searchLink fieldCode="AR" term="%22Lefterov%2C+Iliya%22">Lefterov, Iliya</searchLink><relatesTo>1</relatesTo><i> iliyal@pitt.edu</i><br /><searchLink fieldCode="AR" term="%22Fitz%2C+Nicholas+F%2E%22">Fitz, Nicholas F.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Cronican%2C+Andrea+A%2E%22">Cronican, Andrea A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Fogg%2C+Allison%22">Fogg, Allison</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Lefterov%2C+Preslav%22">Lefterov, Preslav</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Kodali%2C+Ravindra%22">Kodali, Ravindra</searchLink><relatesTo>2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Wetzel%2C+Ronald%22">Wetzel, Ronald</searchLink><relatesTo>2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Koldamova%2C+Radosveta%22">Koldamova, Radosveta</searchLink><relatesTo>1</relatesTo><i> radak@pitt.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. 11/19/2010, Vol. 285 Issue 47, p36945-36957. 13p.
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  Data: A hallmark of Alzheimer disease (AD) is the deposition of amyloid β (Aβ) in brain parenchyma and cerebral blood vessels, accompanied by cognitive decline. Previously, we showed that human apolipoprotein A-I (apoA-I) decreases Aβ40 aggregation and toxicity. Here we demonstrate that apoA-I in lipidated or non-lipidated form prevents the formation of high molecular weight aggregates of Aβ42 and decreases Aβ42 toxicity in primary brain cells. To determine the effects of apoA-I on AD phenotype in vivo, we crossed APP/PS1ΔE9 to apoA-IKO mice. Using a Morris water maze, we demonstrate that the deletion of mouse Apoa-I exacerbates memory deficits in APP/PS1ΔE9 mice. Further characterization of APP/PS1ΔE9/apoA-IKO mice showed that apoA-I deficiency did not affect amyloid precursor protein processing, soluble Aβ oligomer levels, Aβ plaque load, or levels of insoluble Aβ in brain parenchyma. To examine the effect of Apoa-I deletion on cerebral amyloid angiopathy, we measured insoluble Aβ isolated from cerebral blood vessels. Our data show that in APP/PS1ΔE9/apoA-IKO mice, insoluble Aβ40 is increased more than 10-fold, and Aβ42 is increased 1.5-fold. The increased levels of deposited amyloid in the vessels of cortices and hippocampi of APP/PS1ΔE9/apoA-IKO mice, measured by X-34 staining, confirmed the results. Finally, we demonstrate that lipidated and non-lipidated apoA-I significantly decreased Aβ toxicity against brain vascular smooth muscle cells. We conclude that lack of apoA-I aggravates the memory deficits in APP/PS1ΔE9 mice in parallel to significantly increased cerebral amyloid angiopathy. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1074/jbc.M110.127738
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      – Code: eng
        Text: English
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      Pagination:
        PageCount: 13
        StartPage: 36945
    Subjects:
      – SubjectFull: Apolipoproteins
        Type: general
      – SubjectFull: Protein deficiency
        Type: general
      – SubjectFull: Cerebral amyloid angiopathy
        Type: general
      – SubjectFull: Animal models of Alzheimer's disease
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      – SubjectFull: Cerebral circulation
        Type: general
      – SubjectFull: Amyloid beta-protein precursor
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      – SubjectFull: Oligomers
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      – TitleFull: Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1 ΔE9 Mice.
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              Text: 11/19/2010
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