Inhibition of NF-kappa B potentiates amyloid beta-mediated neuronal apoptosis

Kaltschmidt B, Uherek M, Wellmann H, Volk B, Kaltschmidt C (1999)
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 96(16): 9409-9414.

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Abstract
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.
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Kaltschmidt B, Uherek M, Wellmann H, Volk B, Kaltschmidt C. Inhibition of NF-kappa B potentiates amyloid beta-mediated neuronal apoptosis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 1999;96(16):9409-9414.
Kaltschmidt, B., Uherek, M., Wellmann, H., Volk, B., & Kaltschmidt, C. (1999). Inhibition of NF-kappa B potentiates amyloid beta-mediated neuronal apoptosis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 96(16), 9409-9414.
Kaltschmidt, B., Uherek, M., Wellmann, H., Volk, B., and Kaltschmidt, C. (1999). Inhibition of NF-kappa B potentiates amyloid beta-mediated neuronal apoptosis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 96, 9409-9414.
Kaltschmidt, B., et al., 1999. Inhibition of NF-kappa B potentiates amyloid beta-mediated neuronal apoptosis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 96(16), p 9409-9414.
B. Kaltschmidt, et al., “Inhibition of NF-kappa B potentiates amyloid beta-mediated neuronal apoptosis”, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 96, 1999, pp. 9409-9414.
Kaltschmidt, B., Uherek, M., Wellmann, H., Volk, B., Kaltschmidt, C.: Inhibition of NF-kappa B potentiates amyloid beta-mediated neuronal apoptosis. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 96, 9409-9414 (1999).
Kaltschmidt, Barbara, Uherek, M., Wellmann, H., Volk, B., and Kaltschmidt, Christian. “Inhibition of NF-kappa B potentiates amyloid beta-mediated neuronal apoptosis”. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 96.16 (1999): 9409-9414.
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