Restraining tumor necrosis factor-alpha by thalidomide prevents the Amyloid beta-induced impairment of recognition memory in mice

No effective remedy has currently been realized to prevent the cognitive impairments of Alzheimer's disease (AD). The interruption of the toxic pathways of amyloid beta peptide (A beta) still remains promising for the treatment. The involvement of tumor necrosis factor-alpha (TNF-alpha) in the toxicity of A beta(1-40) in recent reports provide a fresh target for the interruption. In the current study, we evaluated the feasibility of a strategy that target TNF-alpha to prevent the impairment of memory induced by A beta. The i.c.v-injection of A beta(25-35) increased the hippocampal mRNA expression of both TNF-a and inducible nitric oxide synthase (iNOS), of which the former was stronger. The knock-out of TNF-alpha (TNF-alpha (-/-)) in mouse prevented the increase of iNOS mRNA induced by A beta(25-35). Not only the inhibition of iNOS activity but also TNF-alpha (-/-) prevented the nitration of proteins in the hippocampus and the impairment of recognition memory in mice induced by A beta(25-35). Daily treatment with thalidomide (20 mg/kg), a preferential degrader of TNF-alpha mRNA, or i.c. v.-injection of an anti-TNF-alpha antibody (10 eta g/mouse) prevented the nitration of proteins in the hippocampus and the impairment of recognition memory induced by A beta(25-35) or A beta(1-40) in mice. These results suggested the practicability of targeting TNF-alpha as a preventive strategy against A beta-mediated cognitive impairments. (c) 2007 Elsevier B.V. All rights reserved.