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A Novel Apolipoprotein E Antagonist Functionally Blocks Apolipoprotein E Interaction With N-terminal Amyloid Precursor Protein, Reduces β-Amyloid-Associated Pathology, and Improves Cognition

  • Author Footnotes
    1 DS, AH, and HH contributed equally to this work.
    Darrell Sawmiller
    Footnotes
    1 DS, AH, and HH contributed equally to this work.
    Affiliations
    Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida
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  • Author Footnotes
    1 DS, AH, and HH contributed equally to this work.
    Ahsan Habib
    Footnotes
    1 DS, AH, and HH contributed equally to this work.
    Affiliations
    Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida
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  • Author Footnotes
    1 DS, AH, and HH contributed equally to this work.
    Huayan Hou
    Footnotes
    1 DS, AH, and HH contributed equally to this work.
    Affiliations
    Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida
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  • Takashi Mori
    Affiliations
    Departments of Biomedical Sciences and Pathology, Saitama Medical Center and Saitama Medical University, Kawagoe, Saitama, Japan
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  • Anran Fan
    Affiliations
    Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida
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  • Jun Tian
    Affiliations
    Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida
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  • Jin Zeng
    Affiliations
    Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida
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  • Brian Giunta
    Affiliations
    Neuroimmunology Laboratory, Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida
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  • Paul R. Sanberg
    Affiliations
    Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, Florida
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  • Mark P. Mattson
    Affiliations
    Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, Maryland

    Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Jun Tan
    Correspondence
    Address correspondence to Jun Tan, M.D., Ph.D., Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33613.
    Affiliations
    Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, Florida
    Search for articles by this author
  • Author Footnotes
    1 DS, AH, and HH contributed equally to this work.

      Abstract

      Background

      The ɛ4 isoform of apolipoprotein E (apoE4) is a major genetic risk factor for the development of sporadic Alzheimer’s disease (AD), and its modification has been an intense focus for treatment of AD during recent years.

      Methods

      We investigated the binding of apoE, a peptide corresponding to its low-density lipoprotein receptor binding domain (amino acids 133–152; ApoEp), and modified ApoEp to amyloid precursor protein (APP) and their effects on amyloid-β (Aβ) production in cultured cells. Having discovered a peptide (6KApoEp) that blocks the interaction of apoE with N-terminal APP, we investigated the effects of this peptide and ApoEp on AD-like pathology and behavioral impairment in 3XTg-AD and 5XFAD transgenic mice.

      Results

      ApoE and ApoEp, but not truncated apoE lacking the low-density lipoprotein receptor binding domain, physically interacted with N-terminal APP and thereby mediated Aβ production. Interestingly, the addition of 6 lysine residues to the N-terminus of ApoEp (6KApoEp) directly inhibited apoE binding to N-terminal APP and markedly limited apoE- and ApoEp-mediated Aβ generation, presumably through decreasing APP cellular membrane trafficking and p44/42 mitogen-activated protein kinase phosphorylation. Moreover, while promoting apoE interaction with APP by ApoEp exacerbated Aβ and tau brain pathologies in 3XTg-AD mice, disrupting this interaction by 6KApoEp ameliorated cerebral Aβ and tau pathologies, neuronal apoptosis, synaptic loss, and hippocampal-dependent learning and memory impairment in 5XFAD mice without altering cholesterol, low-density lipoprotein receptor, and apoE expression levels.

      Conclusions

      These data suggest that disrupting apoE interaction with N-terminal APP may be a novel disease-modifying therapeutic strategy for AD.

      Keywords

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      Linked Article

      • Targeting the Interaction Between Apolipoprotein E and Amyloid Precursor Protein: A Novel Alzheimer’s Disease Therapy
        Biological PsychiatryVol. 86Issue 3
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          The identification of mutations in the amyloid precursor protein (APP) and PSEN1 and PSEN2 that cause autosomal dominantly inherited Alzheimer’s disease (AD) and result in increased production of aggregation-prone forms of amyloid-β (Aβ) established beyond a doubt that APP processing and the production of Aβ peptides are intimately involved in the disease process and led to the proposal of and support for the amyloid cascade hypothesis for AD (1,2). Despite its strengths, the amyloid cascade hypothesis is incomplete without addressing the essential role of amyloid-associated proteins [for reviews, see (3,4)].
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