Amyloid Plaques Dissociate Pentameric to Monomeric C-Reactive Protein: A Novel Pathomechanism Driving Cortical Inflammation in Alzheimer's Disease?

Authors

  • Frederik Strang,

    1. Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
    2. Medizinische Klinik II, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Luebeck, Germany.
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    • F.S and A.S. are equally contributing first authors

  • Amelie Scheichl,

    1. Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
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    • F.S and A.S. are equally contributing first authors

  • Yung-Chih Chen,

    1. Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
    2. Department of Medicine, Monash University, Melbourne, Victoria, Australia.
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  • Xiaowei Wang,

    1. Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
    2. Department of Medicine, Monash University, Melbourne, Victoria, Australia.
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  • Nay-Min Htun,

    1. Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
    2. Department of Medicine, Monash University, Melbourne, Victoria, Australia.
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  • Nicole Bassler,

    1. Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
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  • Steffen U. Eisenhardt,

    1. Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
    2. Department of Plastic and Hand Surgery, University of Freiburg Medical Centre, Germany
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  • Jonathon Habersberger,

    1. Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
    2. Department of Medicine, Monash University, Melbourne, Victoria, Australia.
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    • J.H and K.P. are equally contributing senior authors

  • Karlheinz Peter

    Corresponding author
    1. Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
    2. Department of Medicine, Monash University, Melbourne, Victoria, Australia.
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    • J.H and K.P. are equally contributing senior authors


Karlheinz Peter, MD, PhD, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Vic. 3004, Australia (E-mail: karlheinz.peter@bakeridi.edu.au)

Abstract

Beta-amyloid (Aβ) plaques and local inflammation are central to the pathogenesis of Alzheimer's disease. Although an association between circulating pentameric C-reactive protein (pCRP) and Alzheimer's disease has been reported no pathomechanistic link has been established. We hypothesized that Aβ plaques induce the dissociation of pCRP to individual monomers (mCRP), which possess strong pro-inflammatory properties not shared with pCRP and localizing inflammation to Alzheimer's plaques. pCRP was incubated with Aβ plaques generated in vitro and with non-aggregated Aβ42 peptide. pCRP dissociation to mCRP was found only when co-incubated with Aβ plaques. Furthermore, sections of frontal cortex from brains of patients with and without Alzheimer's disease were stained with antibodies specific for mCRP and pCRP. There was significantly more mCRP in the cortex of Alzheimer's disease patients (P ≤ 0.01). In contrast, there was no significant difference in pCRP staining. These findings establish that Aβ plaques possess a previously unrecognized potential to dissociate pentameric CRP to monomeric CRP. The existence of mCRP but not pCRP in the brains of Alzheimer's disease patients strongly indicates that this newly described biological effect of Aβ plaques is relevant in Alzheimer pathobiology; potentially localizing and amplifying inflammation via the strong pro-inflammatory effects of locally generated mCRP.

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