Alzheimer’s missing link found: Is a promising target for new drugs

Yale School of Medicine researchers have discovered a protein that is the missing link in the complicated chain of events that lead to Alzheimer’s disease, they report in the Sept. 4 issue of the journal Neuron. Researchers also found that blocking the protein with an existing drug can restore memory in mice with brain damage that mimics the disease.

“What is very exciting is that of all the links in this molecular chain, this is the protein that may be most easily targeted by drugs,” said Stephen Strittmatter, the Vincent Coates Professor of Neurology and senior author of the study. “This gives us strong hope that we can find a drug that will work to lessen the burden of Alzheimer’s.”

Scientists have already provided a partial molecular map of how Alzheimer’s disease destroys brain cells. In earlier work, Strittmatter’s lab showed that the amyloid-beta peptides, which are a hallmark of Alzheimer’s, couple with prion proteins on the surface of neurons. By an unknown process, the coupling activates a molecular messenger within the cell called Fyn.

In the Neuron paper, the Yale team reveals the missing link in the chain, a protein within the cell membrane called metabotropic glutamate receptor 5 or mGluR5. When the protein is blocked by a drug similar to one being developed for Fragile X syndrome, the deficits in memory, learning, and synapse density were restored in a mouse model of Alzheimer’s.

Strittmatter stressed that new drugs may have to be designed to precisely target the amyloid-prion disruption of mGluR5 in human cases of Alzheimer’s and said his lab is exploring new ways to achieve this.

20 October 2013

Serial Killer Blocked

The possibility of developing drugs to treat Alzheimer’s disease, the commonest form of dementia, comes closer as we unravel its complex chemistry. We know that a family of substances called amyloid-beta peptides (ABPs) is a serial killer of brain nerve cells, or neurons – whose spindly extremities vulnerable to attack are stained green in this picture of highly magnified brain tissue. While ABPs are difficult to zap with drugs, a much easier target appears to be a protein in the cell membrane, called mGluR5 which has been shown to play a critical role in the ABPs’ attack plan. In an experiment on mice with a similar condition to Alzheimer’s, their memory and learning ability were restored when mGluR5 was chemically blocked. Whether a safe and effective drug can be developed for use on humans remains to be seen but research is now underway.

Written by Mick Warwicker

Yale University, USA
Juha Lauren and Stephen Strittmatter
Research published in Neuron 79(5): 887–902

Citation Assignment

James Hamilton

References:

(Butler, Dodge et al. 2010, Ansoleaga, Montano et al. 2014, Besheer, Fisher et al. 2014, Katz, Pronk et al. 2014, Mulia, Zemore et al. 2014)Ansoleaga, E., et al. (2014). “Psychosocial Risk at Work and Hazardous Alcohol Consumption Among Chile’s Working Adults.” Canadian Journal of Public Health-Revue Canadienne De Sante Publique 104(7): E502-E508.

Besheer, J., et al. (2014). “Stress Hormone Exposure Reduces mGluR5 Expression in the Nucleus Accumbens: Functional Implications for Interoceptive Sensitivity to Alcohol.”
Neuropsychopharmacology 39(10): 2376-2386.

Butler, A. B., et al. (2010). “College Student Employment and Drinking: A Daily Study of Work Stressors, Alcohol Expectancies, and Alcohol Consumption.” Journal of Occupational Health Psychology 15(3): 291-303.

Katz, A. S., et al. (2014). “The Association Between Optimal Lifestyle-Related Health Behaviors and Employee Productivity.” Journal of Occupational and Environmental Medicine 56(7): 708-713.

Mulia, N., et al. (2014). “Economic Loss and Alcohol Consumption and Problems During the 2008 to 2009 U. S. Recession.” Alcoholism-Clinical and Experimental Research 38(4): 1026-1034.

By carefully reading and analyzing these sources, I have found a few common themes and connections.
Most notably:
• Workers who have a weak support system to cope with stresses have a higher rate of alcohol consumption
• Students and adults who work longer hours or more stressful jobs have a higher rate of alcohol consumption
• Workers with higher stress levels have higher levels of alcohol consumption.
• The stress hormone corticosterone decreases human sensitivity to the effects of alcohol; this can lead to increased alcohol consumption.
• Alcohol consumption is antagonized by recent unemployment or wage decrease.
• These factors are extremely interesting because they are very interactive with each other. They pose a serious risk of forming a positive feedback loop that further perpetuates the effects of alcoholism.

I want to further focus my research question. I am weary of the dangers of ‘causation vs. correlation’ when examining the effects of alcohol consumption and work stress. I want to make sure that I hone in on the specific effects of daily stress on a person’s alcohol consumption. To do this I will look further into the biological effects of stress and alcohol so that I can better determine the root of alcoholism in the life of a stressed worker. I want to look at varaibles of stress, long work hours and genetic predisposition to determine the extent to which each one of these plays a role in the development of alcoholism.

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