Evidence that brain-reactive autoantibodies contribute to chronic neuronal internalization of exogenous amyloid-β1-42 and key cell surface proteins during Alzheimer's disease pathogenesis

Eric L. Goldwaser, Nimish K. Acharya, Hao Wu, George A. Godsey, Abhirup Sarkar, Cassandra A. Demarshall, Mary C. Kosciuk, Robert G. Nagele

    Research output: Contribution to journalArticlepeer-review

    1 Scopus citations

    Abstract

    Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer's disease (AD). In the present study, we examined consequences of increased BBB permeability on the development of AD-related pathology by tracking selected leaked plasma components and their interactions with neurons in vivo and in vitro. Histological sections of cortical regions of postmortem AD brains were immunostained to determine the distribution of amyloid-β1-42 (Aβ42), cathepsin D, IgG, GluR2/3, and alpha7 nicotinic acetylcholine receptor (α7nAChR). Results revealed that chronic IgG binding to pyramidal neurons coincided with internalization of Aβ42, IgG, GluR2/3, and α7nAChR as well as lysosomal compartment expansion in these cells in regions of AD pathology. To test possible mechanistic interrelationships of these phenomena, we exposed differentiated SH-SY5Y neuroblastoma cells to exogenous, soluble Aβ42 peptide and serum from AD and control subjects. The rate and extent of Aβ42 internalization in these cells was enhanced by serum containing neuron-binding IgG autoantibodies. This was confirmed by treating cells with individual antibodies specific for α7nAChR, purified IgG from AD or non-AD sera, and sera devoid of IgG, in the presence of 100 nM Aβ42. Initial co-localization of IgG, α7nAChR, and Aβ42 was temporally and spatially linked to early endosomes (Rab11) and later to lysosomes (LAMP-1). Aβ42 internalization was attenuated by treatment with monovalent F(ab) antibody fragments generated from purified IgG from AD serum and then rescued by coupling F(ab) fragments with divalent human anti-Fab. Overall, results suggest that cross-linking of neuron-binding autoantibodies targeting cell surface proteins can accelerate intraneuronal Aβ42 deposition in AD.

    Original languageEnglish (US)
    Pages (from-to)345-361
    Number of pages17
    JournalJournal of Alzheimer's Disease
    Volume74
    Issue number1
    DOIs
    StatePublished - 2020

    All Science Journal Classification (ASJC) codes

    • Neuroscience(all)
    • Clinical Psychology
    • Geriatrics and Gerontology
    • Psychiatry and Mental health

    Fingerprint

    Dive into the research topics of 'Evidence that brain-reactive autoantibodies contribute to chronic neuronal internalization of exogenous amyloid-β<sub>1-42</sub> and key cell surface proteins during Alzheimer's disease pathogenesis'. Together they form a unique fingerprint.

    Cite this