PUB - Publikationen an der Universität Bielefeld

One mechanism leading to neurodegeneration during Alzheimer's disease (AD) is amyloid beta peptide (A beta) neurotoxicity. A beta elicits in cultured central nervous system neurons a biphasic response: a low-dose neurotrophic response and a high-dose neurotoxic response. Previously me reported that NF-kappa B is activated by low doses of A beta only. Here we show that NF-kappa B activation leads to neuroprotection. In primary neurons me found that a pretreatment with 0.1 mu M A beta-(1-40) protects against neuronal death induced with 10 mu M A beta-(1-40). As a known neuroprotective agent we nest analyzed the effect of tumor necrosis factor alpha (TNF-alpha). Maximal activation of NF-kappa B was found with 2 ng/ml TNF-alpha. Pretreatment with TNF-alpha protected cerebellar granule cells from tell death induced by 10 mu M A beta-(1-40). This protection is described by an inverted U-shaped dose response and is maximal with a NF-kappa B-activating dose. The molecular specificity of this protective effect was analyzed by specific blockade of NF-kappa B activation. Overexpression of a transdominant negative I kappa B-alpha blocks NF-kappa B activation and potentiates A beta-mediated neuronal apoptosis. Our findings show that activation of NF-kappa B is the underlying mechanism of the neuroprotective effect of low-dose A beta and TNF-alpha. In accordance with these in vitro data we find that nuclear NF-kappa B immunoreactivity around various plaque stages of AD patients is reduced in comparison to age-matched controls, Taken together these data suggest that pharmacological NF-kappa B activation may be a useful approach in the treatment of AD and related neurodegenerative disorders.