Journal of Alzheimer's Disease : JAD
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.
Goldwaser, Eric L; Acharya, Nimish K; Wu, Hao; Godsey, George A; Sarkar, Abhirup; DeMarshall, Cassandra A; Kosciuk, Mary C; and Nagele, Robert G, "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" (2020). School of Osteopathic Medicine Faculty Scholarship. 156.
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Goldwaser EL, Acharya NK, Wu H, Godsey GA, Sarkar A, DeMarshall CA, Kosciuk MC, Nagele RG. 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. Journal of Alzheimer's Disease: JAD. 2020 Mar 10;74(1):345-361. Epub 2020 Feb 5. doi: 10.3233/JAD-190962. PMID: 32039847. PMCID: PMC7175946.
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