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.
Original language | English |
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Pages (from-to) | 619-629 |
Number of pages | 11 |
Journal | Molecular Immunology |
Volume | 56 |
Issue number | 4 |
DOIs | |
State | Published - 31 Dec 2013 |
Keywords
- Alzheimer's disease
- Cognitive function
- Complement component C5a
- IVIG
- LTP
- PCREB