Adalimumab improves cognitive impairment, exerts neuroprotective effects and attenuates neuroinflammation in an Aβ1-40-injected mouse model of Alzheimer's disease

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-alpha) monoclonal antibody adalimumab can improve cognitive function and reduce AD pathology in A beta(1-40)-injected animal models of AD, as well as the mechanisms underlying the effects of treatment. A beta(1-40)-injected mice treated with adalimumab exhibited significant improvements in memory relative to mice injected with A beta(1-40) alone, as well as decreases in beta secretase-1 (BACE1) protein expression and A beta(1-40) plaques. In addition, adalimumab treatment significantly attenuated neuronal damage and neuroinflammation in A beta(1-40)-injected mice. A beta(1-40)-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-kappa B) p65 signalling. Serine 536 residues of NF-kappa B p65, which is phosphorylated by TNF-alpha, increased along with the degradation of inhibitor of kappa B (I kappa B) in the hippocampus of A beta-injected mice, although these effects were again attenuated by adalimumab. Furthermore, A beta(1-40)-induced increases in TNF-alpha 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.