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Complement‐derived anaphylatoxin, C5a‐mediated signaling pathway is a novel pharmacological target for IVIG‐regulated humoral immunotherapy in Alzheimer's Disease
Author(s) -
Vempati Prashant,
Gong Bing,
Zhao Wei,
Wang Jun,
Devi Lakshmi A,
Pasinetti Giulio M
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.846.5
Subject(s) - c5a receptor , dementia , medicine , anaphylatoxin , immunology , complement system , antibody , disease , immunotherapy , alzheimer's disease , neuroscience , cognitive decline , neuroinflammation , immune system , inflammation , psychology
Human intravenous immunoglobulin (IVIG) has been found to benefit patients with Alzheimer's disease (AD) and other neurodegenerative diseases. According to a common hypothesis, IVIG contains naturally occurring auto antibodies that block the toxic effects of β‐amyloid (Aβ) and promote brain Aβ clearance. However, with the discrepancy between Aβ pathology in postmortem AD brains and the severity of clinical dementia in the elderly, the beneficial effects of IVIG may extend beyond Aβ clearance. We hypothesized that elevated brain levels of complement C5‐derived C5a anaphylatoxins play a crucial role in the regulation of signaling pathways related to learning and memory functions, which contribute to successful aging, and that human intravenous immunoglobulin may have beneficial effects on cognitive function in age‐related dementia by modulating C5a expression in the brain. Our studies show that the levels of C5a are decreased in C57BL6 mice (24–28 month old), and that reduced brain C5a content is correlated with a decline in cognitive function. Most importantly, four weeks of treatment with IVIG in TG2576 mice significantly increased the level of C5a in the brain and improved synaptic plasticity. Given the high safety of IVIG in clinical practice over the past decade and the lack of effective AD therapy, our study would provide novel mechanisms in AD treatment for the elderly. Supported by unrestricted grant to GMP