| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Preconditioning Protects Neurons via Neuron-Specific Up-Regulation of CREB-Binding Protein1
,
* Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612;
Section of Neuroscience, Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE 68583; and
Laboratory of Neurobiology, National Institute on Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709
Despite being a proinflammatory cytokine, TNF-
preconditions neurons against various toxic insults. However, underlying molecular mechanisms are poorly understood. The present study identifies the importance of CREB-binding protein (CBP) in facilitating TNF--mediated preconditioning in neurons. Treatment of rat primary neurons with fibrillar amyloid β1–42 (Aβ) resulted in the loss of CBP protein. However, this loss was compensated by TNF- preconditioning as the expression of neuronal CBP was up-regulated in response to TNF- treatment. The induction of CBP by TNF- was observed only in neurons, but not in astroglia and microglia, and it was contingent on the activation of transcription factor NF-
B. Interestingly, antisense knockdown of CBP abrogated the TNF--mediated preconditioning of neurons against Aβ and glutamate toxicity. Similarly in vivo, preadministration of TNF- in mouse neocortex prevented Aβ-induced apoptosis and loss of choline acetyltransferase-positive cholinergic neurons. However, coadministration of cbp antisense, but not scrambled oligonucleotides, negated the protective effect of TNF- against Aβ neurotoxicity. This study illustrates a novel biological role of TNF- in increasing neuron-specific expression of CBP for preconditioning that may have therapeutic potential against neurodegenerative disorders.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by grants from the National Institutes of Health (Grants NS39940 and NS48923) and the Alzheimer’s Association (Grant IIRG-07-58684) to K.P., the Intramural Research Program of the National Institutes of Health and the National Institute on Environmental Health Sciences (to S.M.D.) and a University of Nebraska Medical Center graduate research assistantship (to R.N.S.).
2 Address correspondence and reprint requests to Dr. Kalipada Pahan, Department of Neurological Sciences, Rush University Medical Center, Cohn Research Building, Suite 320, 1735 West Harrison Street, Chicago, IL 60612. E-mail address: Kalipada_Pahan{at}rush.edu
3 Abbreviations used in this paper: Aβ, amyloid β; CBP, CREB-binding protein; GFAP, glial fibrillary acidic protein; MnSOD, manganese superoxide dismutase; ASO, antisense oligonucleotide; ScO, scrambled oligonucleotide; qPCR, quantitative PCR; NBD, NF-B essential modifier-binding domain; DAPI, 4',6-diamidino-2-phenylindole; ChAT, choline acetyltransferase; NRSF, neuron-restrictive silencer factor; HAT, histone acetyltransferase; HDAC, histone deacetylase.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
