Many studies have implicated accumulation of metals in Alzheimer's pathology and this has been used to justify the use of metal targeted therapies in clinical trials. A quantitative meta-analysis suggests this data has not been consistent and demonstrated a citation bias for papers that found increased iron levels. This study found that cortical copper levels were actually lower and zinc levels were only increased in the parietal lobe. Zinc supplementation may have therapeutic affects associated with decreasing circulating copper levels in Alzheimer's patients. Mechanistic research supports a model where accumulating zinc leads to neuronal cell death by: targeting Amyloid beta to stimulate NMDARs, inhibiting the ferroxidase activity of Amyloid Precursor Protein, and stimulating hyperphosphorylation of Tau. If we accept this pathological role of brain zinc, how can we explain beneficial effects of zinc supplementation?
Article Zinc and the aging brain
Inflammation is thought to be at least a maintaining factor in the pathogenesis of Alzheimer's disease (AD). Ferritin and Abeta co-localize in AD tissue and may act a source of free radicals promoting neurodegeneration.
Zaman, Could you provide a link to research on Ferritin and Abeta?
Data seems to indicate that metal accumulation contributes to alzheimer's pathophysiology. Attached is an article that framework for the metal theory of Alzheimer's disease.
Proteins that participate in alzheimer's pathology interact with many transition metals.
Additionally, Zinc plays a direct role in cell redox homeostasis
http://www.ncbi.nlm.nih.gov/pubmed/22635102
In my opinion finding that metals affect the intensification of Alzheimer's disease, is too general.
I think closer to the correct answer to the question about the interaction between the metals in the body and Alzheimer's disease, we will be when we will recognize the susceptibility of different metals to create complexes with organic compounds of biological importance.
This, in my opinion, is not only the key to the explanation of the disease, but also to it counteract it (treatment).
How Strong? Very Strong
I a have listed just a few refs from our group
1: Rembach A, Hare DJ, Lind M, Fowler CJ, Cherny RA, McLean C, Bush AI, Masters
CL, Roberts BR. Decreased copper in Alzheimer's disease brain is predominantly in
the soluble extractable fraction. Int J Alzheimers Dis. 2013;2013:623241. doi:
10.1155/2013/623241. Epub 2013 Oct 21. PubMed PMID: 24228186; PubMed Central
PMCID: PMC3818847.
2: Hung YH, Bush AI, La Fontaine S. Links between copper and cholesterol in
Alzheimer's disease. Front Physiol. 2013 May 16;4:111. doi:
10.3389/fphys.2013.00111. eCollection 2013. PubMed PMID: 23720634; PubMed Central
PMCID: PMC3655288.
3: Rembach A, Doecke JD, Roberts BR, Watt AD, Faux NG, Volitakis I, Pertile KK,
Rumble RL, Trounson BO, Fowler CJ, Wilson W, Ellis KA, Martins RN, Rowe CC,
Villemagne VL, Ames D, Masters CL, AIBL research group, Bush AI. Longitudinal
analysis of serum copper and ceruloplasmin in Alzheimer's disease. J Alzheimers
Dis. 2013 Jan 1;34(1):171-82. doi: 10.3233/JAD-121474. PubMed PMID: 23168449.
4: Ayton S, Lei P, Bush AI. Metallostasis in Alzheimer's disease. Free Radic Biol
Med. 2013 Sep;62:76-89. doi: 10.1016/j.freeradbiomed.2012.10.558. Epub 2012 Nov
9. Review. PubMed PMID: 23142767.
5: Greenough MA, Camakaris J, Bush AI. Metal dyshomeostasis and oxidative stress
in Alzheimer's disease. Neurochem Int. 2013 Apr;62(5):540-55. doi:
10.1016/j.neuint.2012.08.014. Epub 2012 Sep 8. Review. PubMed PMID: 22982299.
1: Biran Y, Masters CL, Barnham KJ, Bush AI, Adlard PA. Pharmacotherapeutic
targets in Alzheimer's disease. J Cell Mol Med. 2009 Jan;13(1):61-86. doi:
10.1111/j.1582-4934.2008.00595.x. Epub 2008 Nov 18. Review. PubMed PMID:
19040415.
2: Adlard PA, Cherny RA, Finkelstein DI, Gautier E, Robb E, Cortes M, Volitakis
I, Liu X, Smith JP, Perez K, Laughton K, Li QX, Charman SA, Nicolazzo JA, Wilkins
S, Deleva K, Lynch T, Kok G, Ritchie CW, Tanzi RE, Cappai R, Masters CL, Barnham
KJ, Bush AI. Rapid restoration of cognition in Alzheimer's transgenic mice with
8-hydroxy quinoline analogs is associated with decreased interstitial Abeta.
Neuron. 2008 Jul 10;59(1):43-55. doi: 10.1016/j.neuron.2008.06.018. PubMed PMID:
18614028.
3: Barnham KJ, Kenche VB, Ciccotosto GD, Smith DP, Tew DJ, Liu X, Perez K,
Cranston GA, Johanssen TJ, Volitakis I, Bush AI, Masters CL, White AR, Smith JP,
Cherny RA, Cappai R. Platinum-based inhibitors of amyloid-beta as therapeutic
agents for Alzheimer's disease. Proc Natl Acad Sci U S A. 2008 May
13;105(19):6813-8. doi: 10.1073/pnas.0800712105. Epub 2008 May 7. PubMed PMID:
18463291; PubMed Central PMCID: PMC2383936.
4: Barnham KJ, Bush AI. Metals in Alzheimer's and Parkinson's diseases. Curr Opin
Chem Biol. 2008 Apr;12(2):222-8. doi: 10.1016/j.cbpa.2008.02.019. Review. PubMed
PMID: 18342639.
5: Smith DG, Cappai R, Barnham KJ. The redox chemistry of the Alzheimer's disease
amyloid beta peptide. Biochim Biophys Acta. 2007 Aug;1768(8):1976-90. Epub 2007
Feb 9. Review. PubMed PMID: 17433250.
6: Crouch PJ, Barnham KJ, Bush AI, White AR. Therapeutic treatments for
Alzheimer's disease based on metal bioavailability. Drug News Perspect. 2006
Oct;19(8):469-74. Review. PubMed PMID: 17160147.
7: White AR, Barnham KJ, Bush AI. Metal homeostasis in Alzheimer's disease.
Expert Rev Neurother. 2006 May;6(5):711-22. Review. PubMed PMID: 16734519.
1: Adlard PA, Parncutt JM, Finkelstein DI, Bush AI. Cognitive loss in zinc
transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of
Alzheimer's disease? J Neurosci. 2010 Feb 3;30(5):1631-6. doi:
10.1523/JNEUROSCI.5255-09.2010. PubMed PMID: 20130173.
2: Adlard PA, Bica L, White AR, Nurjono M, Filiz G, Crouch PJ, Donnelly PS,
Cappai R, Finkelstein DI, Bush AI. Metal ionophore treatment restores dendritic
spine density and synaptic protein levels in a mouse model of Alzheimer's
disease. PLoS One. 2011 Mar 11;6(3):e17669. doi: 10.1371/journal.pone.0017669.
PubMed PMID: 21412423; PubMed Central PMCID: PMC3055881.
3: Adlard PA, Sedjahtera A, Gunawan L, Bray L, Hare D, Lear J, Doble P, Bush AI,
Finkelstein DI, Cherny RA. A novel approach to rapidly prevent age-related
cognitive decline. Aging Cell. 2013 Oct 28. doi: 10.1111/acel.12178. [Epub ahead
of print] PubMed PMID: 24305557.
Hi Johnathan,
Try this ref: J R Connor et al J. Neuroscience Research, 31, Issue 1, pages 75–83, January 1992
Shahid
I think the papers David Finkelstein cites here show strong pre-clincial scientific support for the theory.
There is an ongoing Phase 2 clinical trial (IAGINE) with Prana's Metal Protein Attenuating Compound (MPAC), PBT2, in patients with pro-dromal or mild Alzheimer's disease. It would be interesting to see if the pre-clinical science is translated into clinical efficacy in patients with Alzheimer's disease.
http://pranabio.com/research-and-development/imagine-trial/
In an earlier 12-week, Phase 2 study, PBT2 was shown significantly reduce the level of Abeta protein in the spinal fluid of treated patients and significantly improved cognitive function 1,2,3
1. Lannfelt et al. “Safety, Efficacy, and biomarker findings of PBT2 in targeting Abeta modifying therapy for Alzheimer’s disease: a controlled Phase 2a, double-blind, randomized, placebo-controlled trial”, Lancet Neurology (2008) vol. 7, pp. 779-86.
2. Lannfelt et al. Errata: Lancet Neurology (2009) vol. 8, pp. 981.
3. Faux et al “PBT2 Rapidly Improves Cognition in Alzheimer's Disease: Additional Phase 2 Analyses”, Journal of Alzheimer’s Disease (2010) vol. 20 pp. 509-516
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