Unraveling Alzheimer’s: Simple small molecules could untangle complex disease

ANN ARBOR, Mich.—New molecular tools developed at the University of Michigan show promise for “cleansing” the brain of amyloid plaques, implicated in Alzheimer’s disease.

A hallmark of Alzheimer’s disease—a neurodegenerative disease with no cure—is the aggregation of protein-like bits known as amyloid-beta peptides into clumps in the brain called plaques. These plaques and their intermediate messes can cause cell death, leading to the disease’s devastating symptoms of memory loss and other mental difficulties.

The mechanisms responsible for the formation of these misfolded proteins and their associations with Alzheimer’s disease are not entirely understood, but it’s thought that copper and zinc ions are somehow involved.

The research, led by assistant professor Mi Hee Lim, was published online Dec. 3 in the Proceedings of the National Academy of Sciences.

In earlier work, Lim and her team developed dual-purpose molecular tools that both grab metal ions and interact with amyloid-beta. The researchers went on to show that in solutions with or without living cells, the molecules were able to regulate copper-induced amyloid-beta aggregation, not only disrupting the formation of clumps, but also breaking up clumps that already had formed.

Building upon that first generation of compounds, Lim and lab members Jung-Suk Choi and Joseph Braymer now report a second generation of compounds that are more stable in biological environments. The researchers tested one of those compounds, described in the PNAS paper, in homogenized brain tissue samples from Alzheimer’s disease patients.

“We found that our compound is capable of disassembling the misfolded amyloid clumps to form smaller amyloid pieces, which might be ‘cleansed’ from the brain more easily, demonstrating a therapeutic application of our compound,” said Lim, who has joint appointments in the Life Sciences Institute and the Department of Chemistry. In addition, preliminary tests show that the bi-functional small molecules have a strong potential to cross the blood-brain barrier, the barricade of cells that separates brain tissue from circulating blood, protecting the brain from harmful substances in the bloodstream.

“Crossing this barrier is essential for any treatment like this to be successful,” Lim said.

Next steps include more intensive testing of the new compounds for diagnostic and therapeutic properties.

Lim and her team collaborated with Ayyalusamy Ramamoorthy, professor of chemistry and biophysics on this work, with funding from the U-M Horace H. Rackham School of Graduate Studies, the Alzheimer’s Art Quilt Initiative, and the National Institutes of Health.

Read the article:
http://www.pnas.org/content/early/2010/12/02/1006091107.full.pdf+html?sid=5e3348f1-8fa4-4e0a-ba07-573098113c9a

Visit the Lim lab: http://www.lsi.umich.edu/facultyresearch/labs/lim



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3 thoughts on “Unraveling Alzheimer’s: Simple small molecules could untangle complex disease”

  1. Further to the above comment regarding copper, the Univ. of Rochester Medical Center in 2007 published “Copper Damages Protein that Defends Against Alzheimer’s” :

    The team found that copper damages a molecule known as LRP (low-density lipoprotein receptor-related protein), a molecule that acts like an escort service in the brain, shuttling amyloid-beta out of the brain and into the body

    http://www.urmc.rochester.edu/news/story/index.cfm?id=1718

  2. Mercury exposure has been strongly implicated in AD :”A very strong component of AD researchers believe that amyloid protein is the cause of AD. Therefore, mercury exposure at nanomolar levels causes neuroblastoma cells to produce a protein that is believed to be involved directly in AD. However, this data supports the initial contention from the Haley laboratory that mercury first inhibits enzymes like tubulin, creatine kinase and glutamine synthetase and dramatically affects metabolism. After these inhibitions occur the cell responds to the cytotoxicity by producing and secreting amyloid protein which forms the amyloid plaques observed on brain pathology and used to substantiate the AD diagnosis. To the point, amyloid plaques are the result of AD, not the cause. The cause is exposure to environmental toxicants like mercury.”
    http://www.holistic-dentistry.com/artalzeimer.asp

    The article mentions copper and zinc – well, I´m not a scientist, but I know mercury toxicity elevates copper levels, and zinc is an antagonist of mercury.

    Instead of trying to find a “cure” for AD, how about the FDA and EPA treating mercury for what it is, one of the most toxic elements of all, second to plutonium. They have a responsibility to prohibit the use of mercury dental amalagrams as other countries like Sweden, Norway and Denmark have already done. The FDA must admit the toxicity of mercury for once and for all in vaccines and dental amalgams (50% mercury).

  3. UCLA scientists and colleagues from UC Riverside and the Human BioMolecular Research Institute have found that a form of vitamin D, together with a chemical found in turmeric spice called curcumin, may help stimulate the immune system to clear the brain of amyloid beta, which forms the plaques considered the hallmark of Alzheimer’s disease.

    The team discovered that curcuminoids enhanced the surface binding of amyloid beta to macrophages and that vitamin D STRONGLY stimulated the uptake and absorption of amyloid beta in macrophages in a majority of patients.

    http://www.sciencedaily.com/releases/2009/07/090715131558.htm

    The research was printed in the Journal Of Alzheimer’s, July 2009

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