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A Shift in Microglial β-Amyloid Binding in Alzheimer's Disease Is Associated with Cerebral Amyloid Angiopathy

Authors

  • Matthew Zabel,

    1. Neurosurgery Center for Research, Training and Education, Loma Linda University, Loma Linda, CA
    2. Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA
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  • Matthew Schrag,

    1. Neurosurgery Center for Research, Training and Education, Loma Linda University, Loma Linda, CA
    2. Department of Neurology, Yale University, New Haven, CT
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  • Andrew Crofton,

    1. Neurosurgery Center for Research, Training and Education, Loma Linda University, Loma Linda, CA
    2. Department of Pathology and Human Anatomy, Loma Linda University School of Medicine, Loma Linda, CA
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  • Spencer Tung,

    1. Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
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  • Pierre Beaufond,

    1. Neurosurgery Center for Research, Training and Education, Loma Linda University, Loma Linda, CA
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  • Jon Van Ornam,

    1. Neurosurgery Center for Research, Training and Education, Loma Linda University, Loma Linda, CA
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  • Angie DiNinni,

    1. Neurosurgery Center for Research, Training and Education, Loma Linda University, Loma Linda, CA
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  • Harry V. Vinters,

    1. Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
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  • Giovanni Coppola,

    1. Department of Neurology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA
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  • Wolff M. Kirsch

    Corresponding author
    • Neurosurgery Center for Research, Training and Education, Loma Linda University, Loma Linda, CA
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Corresponding author:

Wolff M. Kirsch, MD, Neurosurgery Center for Research, Training and Education, Loma Linda University, 11234 Anderson St., Rm. A537, Loma Linda, CA 92354 (E-mail: wkirsch@llu.edu)

Abstract

Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) are two common pathologies associated with β-amyloid (Aβ) accumulation and inflammation in the brain; neither is well understood. The objective of this study was to evaluate human post-mortem brains from AD subjects with purely parenchymal pathology, and those with concomitant CAA (and age-matched controls) for differential expression of microglia-associated Aβ ligands thought to mediate Aβ clearance and the association of these receptors with complement activation. Homogenates of brain parenchyma and enriched microvessel fractions from occipital cortex were probed for levels of C3b, membrane attack complex (MAC), CD11b and α-2-macroglobulin and immunoprecipitation was used to immunoprecipitate (IP) CD11b complexed with C3b and Aβ. Both C3b and MAC were significantly increased in CAA compared to AD-only and controls and IP showed significantly increased CD11b/C3b complexes with Aβ in AD/CAA subjects. Confocal microscopy was used to visualize these interactions. MAC was remarkably associated with CAA-affected blood vessels compared to AD-only and control vessels. These findings are consistent with an Aβ clearance mechanism via microglial CD11b that delivers Aβ and C3b to blood vessels in AD/CAA, which leads to Aβ deposition and propagation of complement to the cytolytic MAC, possibly leading to vascular fragility.

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