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Alzheimer's 'Missing Link' Found: Promising Target for New Drugs
Myriam
Posted: Wednesday, September 4, 2013 1:55 PM
Joined: 12/6/2011
Posts: 3326


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. 

 

Other Yale authors are Ji Won Um, Adam C. Kaufman, Mikhail Kostylev, Jacqueline K. Heiss, Massimiliano Stagi, Hideyuki Takahashi, Meghan E. Kerrisk, Alexander Vortmeyer, Thomas Wisniewski, Anthony J. Koleske, Erik C. Gunther and Haakon B. Nygaard. 

The research was funded by the National Institutes of Health.  


Lane Simonian
Posted: Saturday, September 14, 2013 10:48 AM
Joined: 12/12/2011
Posts: 4854


If this research is extended a little bit then the missing link for Alzheimer's disease has likely been found.  Metabotropic glutamate receptor-5 is a g protein-coupled receptor and Fyn is a tyrosine kinase.  The activation of any g protein-coupled receptor or any tyrosine kinase can increase the risk for Alzheimer's disease. 

 

G protein-coupled receptors and receptor tyrosine kinase receptors activate phospholipase C which activates protein kinase C and can lead to the release of intracellular calcium.  Tyrosine kinase receptors and protein kinase C lead to the activation of Src kinases of which Fyn is one.  This results in the BACE1 cut of the secreted amyloid precursor protein--the first step in the formation of amyloid plaques. 

 

http://www.ncbi.nlm.nih.gov/pubmed?cmd=Search&doptcmdl=Citation&defaultField=Title%20Word&term=Zou%5Bauthor%5D%20AND%20Receptor%20tyrosine%20kinases%20positively%20regulate%20BACE%20activity%20and%20Amyloid-beta%20production%20through%20enhancing%20BACE%20internalization 

 

The second cut of the amyloid precursor protein requires high levels of intracellular calcium. 

 

Protein kinase C is needed for the first cut (creating a C-terminal fragment) and for the production of peroxynitrites.  This is all that is required for Alzheimer's disease.  

 

In contrast,we find that PKC activation in human primary neurons

increases the rate of sAPP release and the production of APP 

C-terminal fragments...

 

http://www.jneurosci.org/content/18/8/2907.full.pdf 

 

One of the pathophysiological features of Alzheimer's disease is astrocytosis around senile plaques. Reactive astrocytes may produce proinflammatory mediators, nitric oxide, and subsequent reactive oxygen intermediates such as peroxynitrites...These suggest that CT-APP may participate in Alzheimer's pathogenesis through MAPKs- and NF-kappaB-dependent astrocytosis and iNOS induction.

 

http://www.ncbi.nlm.nih.gov/pubmed/11432978 

 

Amyloid plaques have long been thought to be the cause of neuron loss in Alzheimer’s disease.  Now researchers report that excess of mutated amyloid precursor protein (APP) inside the neurons is sufficient to induce neuron death.  The report challenges the notion that amyloid deposits outside of the cells are necessary for neuron death in Alzheimer’s disease.

 

http://www.sciencedebate.com/science-blog/alzheimer-s-disease-without-amyloid-plaques 

 

Protein kinase C activation can be inhibited by a Mediterranean diet high in polyphenols and omega 3-fatty acids.  Peroxynitrites can be scavenged by phenolic compounds.  There is a lot of complicated medical jargon but it is likely as simple as that.