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PMID: 12608703 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The induction of the TNFalpha death domain signaling pathway in Alzheimer's disease brain.

Neurochemical research ·Vol. 28 ·No. 2 ·2003-02-00 ·Pages 307-18

Zhao M, Cribbs DH, Anderson AJ, Cummings BJ, Su JH, Wasserman AJ, Cotman CW

Abstract

The tumor necrosis factor-alpha death domain pathway contributes to cellular degeneration in a variety of conditions. This study investigates the hypothesis that this death domain pathway is progressively induced in the brain during the progression of Alzheimer's disease (AD). AD cases had increased levels of proapoptotic markers including tumor necrosis factor-alpha (TNFalpha), TNF receptor type 1 (TNF-R1), TNF receptor-associated death domain (TRADD), and caspase-3, 2- to 10-fold higher (P < .01) than age-matched controls and 1 to 3 times higher than transitional cases. In striking contrast, potentially neuroprotective TNF receptor type 2 (TNF-R2), and Fas-associated death domain-like interleukin-1beta-converting enzyme (FLICE) inhibitor protein (FLIP) were decreased in AD as compared with age-matched control cases (P < .01). Overall, there was an elevation in proapoptotic elements, including a 5-fold increase in TNF-R1 and a 12-fold decrease in FLIP in AD brains. These changes may translate to increased degenerative potential because the downstream effector caspase-3 and product of the TNF pathway was also increased in parallel with enhanced TNF proapoptotic conditions. Our findings suggest that the TNF death receptor pathway and caspases are activated in the early stages of neuronal degeneration in AD.

MeSH Terms
Alzheimer Disease/metabolism,pathology Brain/metabolism,pathology Humans Immunohistochemistry Proteins/metabolism Signal Transduction TNF Receptor-Associated Factor 1
Chemicals
Proteins TNF Receptor-Associated Factor 1
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Zhao Ming
Institute for Brain Aging and Dementia, University of California Irvine, Irvine, California, USA.
Cribbs David H
Anderson Aileen J
Cummings Brian J
Su Joseph H
Wasserman Andrea J
Cotman Carl W
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Article Info
Journal
Neurochemical research
Abbr.
Neurochem Res
ISSN
0364-3190
DOI
10.1023/a:1022337519035
Published
2003-02-00
Pages
307-18
Language
English
Region
United States
NLM ID
7613461
Subset
IM
Grants
NIA NIH HHS · AG00538 · United States
NIA NIH HHS · AG17765 · United States
External Links
PubMed source DOI: 10.1023/a:1022337519035 View journal details
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