The pathogenesis of Alzheimer's disease (AD) is associated with an increased inflammatory response via activated microglia and astrocytes. In the present study, we investigated whether treatment with the anti-tumor necrosis factor alpha (TNF-α) monoclonal antibody adalimumab can improve cognitive function and reduce AD pathology in Aβ1-40-injected animal models of AD, as well as the mechanisms underlying the effects of treatment. Aβ1-40-injected mice treated with adalimumab exhibited significant improvements in memory relative to mice injected with Aβ1-40 alone, as well as decreases in beta secretase-1 (BACE1) protein expression and Aβ1-40 plaques. In addition, adalimumab treatment significantly attenuated neuronal damage and neuroinflammation in Aβ1-40-injected mice. Aβ1-40-induced decreases in brain-derived neurotrophic factor (BDNF) expression were also attenuated by treatment with adalimumab. Our experiments further verified that the effects of adalimumab are mediated by nuclear factor kappa B (NF-κB) p65 signalling. Serine 536 residues of NF-κB p65, which is phosphorylated by TNF-α, increased along with the degradation of inhibitor of κB (IκB) in the hippocampus of Aβ-injected mice, although these effects were again attenuated by adalimumab. Furthermore, Aβ1-40-induced increases in TNF-α and interleukin (IL)-6 expression were decreased by treatment with adalimumab. Our results indicate that adalimumab may be clinically useful in human patients with AD.
Keywords: Alzheimer's disease; adalimumab; neuroinflammation; neuroprotection.
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