PMID- 15105262
OWN - NLM
STAT- MEDLINE
DCOM- 20040519
LR  - 20190616
IS  - 0077-8923 (Print)
IS  - 0077-8923 (Linking)
VI  - 1012
DP  - 2004 Mar
TI  - Redox-active metals, oxidative stress, and Alzheimer's disease pathology.
PG  - 153-63
AB  - Considerable evidence is mounting that dyshomeostasis of the redox-active 
      biometals, Cu and Fe, and oxidative stress contribute to the neuropathology of 
      Alzheimer's disease (AD). Present data suggest that metals can interact directly 
      with Abeta peptide, the principal component of beta-amyloid that is one of the 
      primary lesions in AD. The binding of metals to Abeta modulates several 
      physiochemical properties of Abeta that are thought to be central to the 
      pathogenicity of the peptide. First, we and others have shown that metals can 
      promote the in vitro aggregation into tinctorial Abeta amyloid. Studies have 
      confirmed that insoluble amyloid plaques in postmortem AD brain are abnormally 
      enriched in Cu, Fe, and Zn. Conversely, metal chelators dissolve these 
      proteinaceous deposits from postmortem AD brain tissue and attenuate cerebral 
      Abeta amyloid burden in APP transgenic mouse models of AD. Second, we have 
      demonstrated that redox-active Cu(II) and, to a lesser extent, Fe(III) are 
      reduced in the presence of Abeta with concomitant production of reactive oxygen 
      species (ROS), hydrogen peroxide (H(2)O(2)) and hydroxyl radical (OH*). These 
      Abeta/metal redox reactions, which are silenced by redox-inert Zn(II), but 
      exacerbated by biological reducing agents, may lead directly to the widespread 
      oxidation damages observed in AD brains. Moreover, studies have also shown that 
      H(2)O(2) mediates Abeta cellular toxicity and increases the production of both 
      Abeta and amyloid precursor protein (APP). Third, the 5' untranslated region 
      (5'UTR) of APP mRNA has a functional iron-response element (IRE), which is 
      consistent with biochemical evidence that APP is a redox-active metalloprotein. 
      Hence, the redox interactions between Abeta, APP, and metals may be at the heart 
      of a pathological positive feedback system wherein Abeta amyloidosis and 
      oxidative stress promote each other. The emergence of redox-active metals as key 
      players in AD pathogenesis strongly argues that amyloid-specific metal-complexing 
      agents and antioxidants be investigated as possible disease-modifying agents for 
      treating this horrible disease.
FAU - Huang, Xudong
AU  - Huang X
AD  - Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Department of 
      Psychiatry, Massachusetts General Hospital and Harvard Medical School, 
      Charlestown, Massachusetts 02129, USA. huangx@helix.mgh.harvard.edu
FAU - Moir, Robert D
AU  - Moir RD
FAU - Tanzi, Rudolph E
AU  - Tanzi RE
FAU - Bush, Ashley I
AU  - Bush AI
FAU - Rogers, Jack T
AU  - Rogers JT
LA  - eng
GR  - 5-K01-MH02001/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PT  - Review
PL  - United States
TA  - Ann N Y Acad Sci
JT  - Annals of the New York Academy of Sciences
JID - 7506858
RN  - 0 (Amyloid)
RN  - 0 (Antioxidants)
RN  - 0 (Chelating Agents)
RN  - 0 (Metals)
SB  - IM
MH  - Alzheimer Disease/drug therapy/*metabolism/*pathology
MH  - Amyloid/metabolism
MH  - Animals
MH  - Antioxidants/therapeutic use
MH  - Chelating Agents/therapeutic use
MH  - Humans
MH  - Metals/*metabolism
MH  - Oxidation-Reduction
MH  - *Oxidative Stress
RF  - 95
EDAT- 2004/04/24 05:00
MHDA- 2004/05/20 05:00
CRDT- 2004/04/24 05:00
PHST- 2004/04/24 05:00 [pubmed]
PHST- 2004/05/20 05:00 [medline]
PHST- 2004/04/24 05:00 [entrez]
AID - 10.1196/annals.1306.012 [doi]
PST - ppublish
SO  - Ann N Y Acad Sci. 2004 Mar;1012:153-63. doi: 10.1196/annals.1306.012.