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
JournalJournal of Alzheimer's Disease
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AbstractBlood-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.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85081999452&doi=10.3233%2fJAD-190962&partnerID=40&md5=3ce3f1d25ea9fbcbff1389aa5dce2360; http://hdl.handle.net/10713/12470
- Targeting the alpha 7 nicotinic acetylcholine receptor to reduce amyloid accumulation in Alzheimer's disease pyramidal neurons.
- Authors: D'Andrea MR, Nagele RG
- Issue date: 2006
- Increased Aβ<sub>42</sub>-α7-like nicotinic acetylcholine receptor complex level in lymphocytes is associated with apolipoprotein E4-driven Alzheimer's disease pathogenesis.
- Authors: Wang HY, Trocmé-Thibierge C, Stucky A, Shah SM, Kvasic J, Khan A, Morain P, Guignot I, Bouguen E, Deschet K, Pueyo M, Mocaer E, Ousset PJ, Vellas B, Kiyasova V
- Issue date: 2017 Jul 27
- Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-β(1-42) deposition.
- Authors: Nagele RG, Clifford PM, Siu G, Levin EC, Acharya NK, Han M, Kosciuk MC, Venkataraman V, Zavareh S, Zarrabi S, Kinsler K, Thaker NG, Nagele EP, Dash J, Wang HY, Levitas A
- Issue date: 2011
- Mitogen-activated protein kinase signaling pathways are involved in regulating α7 nicotinic acetylcholine receptor-mediated amyloid-β uptake in SH-SY5Y cells.
- Authors: Yang WN, Ma KG, Chen XL, Shi LL, Bu G, Hu XD, Han H, Liu Y, Qian YH
- Issue date: 2014 Oct 10
- Mitogen-activated protein kinase signaling pathways promote low-density lipoprotein receptor-related protein 1-mediated internalization of beta-amyloid protein in primary cortical neurons.
- Authors: Yang WN, Ma KG, Qian YH, Zhang JS, Feng GF, Shi LL, Zhang ZC, Liu ZH
- Issue date: 2015 Jul