当前位置： SCI文献检索 > MOLECULAR IMMUNOLOGY期刊下所有文献 > IVIG immunotherapy protects against synaptic dysfunction in Alzheimer's disease through complement anaphylatoxin C5a-mediated AMPA-CREB-C/EBP signaling pathway.

IVIG immunotherapy protects against synaptic dysfunction in Alzheimer's disease through complement anaphylatoxin C5a-mediated AMPA-CREB-C/EBP signaling pathway.

Abstract：

BACKGROUND:Complement component C5-derived C5a locally generated in the brain has been shown to protect against glutamate-induced neuronal apoptosis and beta-amyloid (Aβ) toxicity, but the mechanism is not clear. In this study, we tested the hypothesis that C5a influences upstream signal transduction pathways associated with cAMP-response element-binding protein (CREB) activation, in which alterations of CREB levels are associated with cognitive deterioration in AD. METHODS:CREB signaling pathway, synaptic plasticity and cognitive function were studied in C5a receptor knockout mice (C5aR(-/-)), C5a over expressing mice (C5a/GFAP) and in Tg2576 mice, an AD mouse model. RESULTS:(1) Cognitive function is severely impaired in C5aR(-/-) mice, coincident with the down-regulated CREB/CEBP pathway in brain. (2) Either the application of recombinant-human-C5a (hrC5a) or exogenous expression of C5a in the brain of a mouse model (C5a/GFAP) enhances this pathway. (3) Application of hrC5a in brain slices from Tg2576 mice significantly improves deficits in long-term potentiation (LTP), while this effect is blocked by a specific AMPA receptor antagonist. (4) Searching for a pharmacological approach to locally mediate C5a responses in the brain, we found that low-dose human intravenous immunoglobulin (IVIG) treatment improves synaptic plasticity and cognitive function through C5a-mediated induction of the CREB/CEBP pathway, while the levels of Aβ in the brain are not significantly affected. CONCLUSION:This study for the first time provides novel evidence suggesting that C5a may beneficially influence cognitive function in AD through an up-regulation of AMPA-CREB signaling pathway. IVIG may systematically improve cognitive function in AD brain by passing Aβ toxicity.

journal_name

Mol Immunol

journal_title

Molecular immunology

authors

Gong B,Pan Y,Zhao W,Knable L,Vempati P,Begum S,Ho L,Wang J,Yemul S,Barnum S,Bilski A,Gong BY,Pasinetti GM

doi

10.1016/j.molimm.2013.06.016

subject

Has Abstract

pub_date

2013-12-01 00:00:00

pages

619-29

issue

4

eissn

0161-5890

issn

1872-9142

pii

S0161-5890(13)00435-5

journal_volume

56

pub_type

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