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PMID: 10430956 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Inhibition of NF-kappaB potentiates amyloid beta-mediated neuronal apoptosis.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 16 ·1999-08-03 ·Pages 9409-14

Kaltschmidt B, Uherek M, Wellmann H, Volk B, Kaltschmidt C

Abstract

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

MeSH Terms
Amyloid beta-Peptides/pharmacology Animals Apoptosis/drug effects,physiology Cells, Cultured Cerebellum/cytology,physiology DNA-Binding Proteins/genetics,physiology Humans I-kappa B Proteins NF-KappaB Inhibitor alpha NF-kappa B/antagonists & inhibitors Neurons/cytology,drug effects,physiology Neuroprotective Agents/pharmacology Peptide Fragments/pharmacology Plaque, Amyloid/pathology Rats Recombinant Proteins/metabolism,pharmacology Transfection Tumor Necrosis Factor-alpha/pharmacology
Chemicals
Amyloid beta-Peptides DNA-Binding Proteins I-kappa B Proteins NF-kappa B NFKBIA protein, human Neuroprotective Agents Nfkbia protein, rat Peptide Fragments Recombinant Proteins Tumor Necrosis Factor-alpha amyloid beta-protein (1-40) NF-KappaB Inhibitor alpha
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Kaltschmidt B
Molecular Neurobiology Laboratory, Institute of Anatomy, Albert-Ludwigs-University, Stefan-Meier-Strasse 19, D-79104 Freiburg, Germany. kaltschm@ruf.uni-freiburg.de
Uherek M
Wellmann H
Volk B
Kaltschmidt C
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.16.9409
Email
kaltschm@ruf.uni-freiburg.de
Published
1999-08-03
Pages
9409-14
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC17796
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.96.16.9409 PMC Full Text View journal details
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