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  • Title: Restraining tumor necrosis factor-alpha by thalidomide prevents the amyloid beta-induced impairment of recognition memory in mice.
    Author: Alkam T, Nitta A, Mizoguchi H, Saito K, Seshima M, Itoh A, Yamada K, Nabeshima T.
    Journal: Behav Brain Res; 2008 May 16; 189(1):100-6. PubMed ID: 18325608.
    Abstract:
    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 (Abeta) still remains promising for the treatment. The involvement of tumor necrosis factor-alpha (TNF-alpha) in the toxicity of Abeta(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 Abeta. The i.c.v-injection of Abeta(25-35) increased the hippocampal mRNA expression of both TNF-alpha 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 Abeta(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 Abeta(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 etag/mouse) prevented the nitration of proteins in the hippocampus and the impairment of recognition memory induced by Abeta(25-35) or Abeta(1-40) in mice. These results suggested the practicability of targeting TNF-alpha as a preventive strategy against Abeta-mediated cognitive impairments.
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