Sparks DL, Lochhead J, Horstman D, Wagoner T, Martin T.
Water quality has a pronounced effect on cholesterol-induced accumulation of Alzheimer amyloid beta (Abeta) in rabbit brain.
J Alzheimers Dis. 2002 Dec;4(6):523-9.
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Copper, Cholesterol and Amyloid-β Deposition
Sparks and colleagues report the effect of dietary water quality on the deposition of amyloid plaques in non-treated and cholesterol-fed rabbits. Maintenance of rabbits on tap water versus distilled water resulted in marked variations in neuronal amyloid-β deposition. The results indicate for the first time the importance of dietary water quality in the deposition of neuronal Aβ. The current study provides in vivo evidence for a role of copper in regulating neuronal Aβ aggregation following cholesterol-induced Aβ generation from AβPP. Although it remains to be determined what water constituent (small organic or a metal ion) is responsible for regulating Aβ deposition, the authors present evidence that points towards copper ions (and zinc ions) as being the culprit.
It is well established that copper ions bind to and regulate the aggregation of Aβ in vitro (Atwood et al., 1998; Abstract 2000). Indirect evidence also has been put forward indicating that copper ions promote Aβ generation in vivo (Cherny et al., 1999; Cherny et al., 2001). The present study adds further support to this idea. Zinc ions also are known to bind to and induce Aβ aggregation (Bush et al., 1994). A recent study showing that ZnT3 knockout mice (decreased neuronal Zn levels) when crossed with AβPP-transgenic mice resulted in a ~70 percent reduction in amyloid plaques (Lee et al., 2002), strongly supports the previous in vitro studies.
Copper and zinc ions compete for metal-binding sites on Aβ (Atwood et al., 2000) suggesting a complex interaction, one where increased copper under mildly acidotic conditions would push the balance towards copper binding and Aβ aggregation (Atwood et al., 2000). Our recent finding that copper is complexed to Aβ in senile plaque cores isolated from AD brains further supports the role of copper in amyloidosis (Dong et al., 2003).
The effect of metal ion, Aβ and cholesterol interactions on cholesterol metabolism is complex, but recent evidence suggests that cholesterol bilayers stabilize metal bound Aβ in an a-helical conformation, whereas Aβ that is not stabilized in this manner forms a β-sheet (Curtain et al., 2003). That Aβ insertion into membranes is prevented by copper ions between pH 6.5-7.5 suggests a possible mechanism of β-sheet formation (Curtain et al., 2003) and amyloid deposition such as seen in the present study. Questions that remain are how and why copper ions present in water (uncomplexed?) are transported to the brain thereby inducing Aβ deposition.
Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, Hartshorn MA, Tanzi RE, Bush AI.
Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis.
J Biol Chem. 1998 May 22;273(21):12817-26.
Atwood CS, Scarpa RC, Huang X, Moir RD, Jones WD, Fairlie DP, Tanzi RE, Bush AI.
Characterization of copper interactions with alzheimer amyloid beta peptides: identification of an attomolar-affinity copper binding site on amyloid beta1-42.
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Bush AI, Pettingell WH, Paradis MD, Tanzi RE.
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Cherny RA, Legg JT, McLean CA, Fairlie DP, Huang X, Atwood CS, Beyreuther K, Tanzi RE, Masters CL, Bush AI.
Aqueous dissolution of Alzheimer's disease Abeta amyloid deposits by biometal depletion.
J Biol Chem. 1999 Aug 13;274(33):23223-8.
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Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice.
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Curtain CC, Ali FE, Smith DG, Bush AI, Masters CL, Barnham KJ.
Metal ions, pH, and cholesterol regulate the interactions of Alzheimer's disease amyloid-beta peptide with membrane lipid.
J Biol Chem. 2003 Jan 31;278(5):2977-82.
Dong J, Atwood CS, Anderson VE, Siedlak SL, Smith MA, Perry G, Carey PR.
Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence.
Biochemistry. 2003 Mar 18;42(10):2768-73.
Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY.
Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice.
Proc Natl Acad Sci U S A. 2002 May 28;99(11):7705-10.