From: unk...@googlegroups.com   
      
   Blood Vessel Damage Plays Key Role in Alzheimer's-related Dementia   
      
   For many years, scientists have known that degeneration of neurons -- nerve   
   cells that transmit signals to and from the brain -- caused Alzheimer's   
   dementia, an incurable disease afflicting more than 35 million people   
   worldwide and approaching epidemic    
   proportions. Now, a new study from Weill Cornell Medical College reveals that   
   changes occurring in blood vessels also play a major role -- by limiting the   
   supply of oxygen and glucose to the brain and contributing to the neuronal   
   damage causing the    
   disease.   
      
   	    
      
   	   
   Stress fibers developing in one of the endothelial cells that line cerebral   
   blood vessels. This cell has been exposed to beta-amyloid, a protein fragment   
   involved in Alzheimer's disease.    
   Image credit: Dr. L. Park    
      
      
   Amyloid-beta -- a protein fragment that accumulates in the brains of   
   Alzheimer's patients -- alters the normal function of neurons and sets the   
   stage for dementia to develop. At the same time, it also acts directly on   
   endothelial cells, the cells lining    
   blood vessels that control the delivery of oxygen and glucose to the brain,   
   thereby damaging their DNA, or genetic makeup, according to the study   
   published Oct. 29 in Nature Communications.   
      
   Certain repair processes are put in place to override the damage, including   
   activation of the DNA repair enzyme poly(ADP)-ribose polymerase, which ends up   
   producing large amounts of the chemical ADP-ribose. ADP-ribose, in turn,   
   activates a cellular    
   surface channel -- known as transient receptor potential melastatin-2 (TRPM2)   
   -- unleashing a flood of calcium ions into the endothelial cells. This sudden   
   and massive calcium overload cripples the endothelial cells and disrupts the   
   supply of blood to    
   the brain, resulting in insufficient delivery of vital oxygen and glucose to   
   the working brain cells.   
      
   "The brain blood vessels become unable to supply the oxygen and nutrients   
   needed to fuel the most energy-demanding brain functions, such as learning and   
   memory," says the senior author of the study, Dr. Costantino Iadecola,   
   director of the Feil Family    
   Brain and Mind Research Institute and the Anne Parrish Titzell Professor of   
   Neurology.   
      
   The research, conducted in mice, identified a mechanism by which this   
   amyloid-beta peptide impedes the regulation of blood flow to the brain. It   
   also highlighted TRPM2 channels as a potential therapeutic target to   
   counteract cerebrovascular dysfunction    
   in Alzheimer's dementia and related conditions. Drugs are being developed that   
   act on this channel to rescue the dysfunction of endothelial cells, enhance   
   blood-flow delivery to the energy-deprived brain and delay disease progression.   
      
   Controlling hypertension, diabetes and obesity -- so-called vascular risk   
   factors -- also may retard the progression and reduce the risk of Alzheimer's   
   dementia, Dr. Iadecola says. Studies in which patients have been carefully   
   monitored for decades have    
   revealed that people who have these vascular risk factors in their 50s and 60s   
   have an increased risk of developing Alzheimer's later in life.   
      
   About half of patients with an Alzheimer's diagnosis also have brain damage   
   resulting from insufficient blood flow, indicating that the blood vessel   
   alterations that contribute to stroke also could accelerate Alzheimer's   
   decline, Dr. Iadecola says.    
   Autopsy studies have confirmed that stroke and Alzheimer's pathologies often   
   coexist in the same brain.   
      
   "No one knows why exactly," Dr. Iadecola says. "But most likely, as you get   
   older, especially if vascular risk factors are present, you also tend to have   
   more damage to your blood vessels, which favors accumulation of amyloid beta   
   in the brain. In turn,    
   amyloid beta causes even more damage to blood vessels and further reduces   
   their ability to nourish the brain. It's a vicious cycle that eventually harms   
   brain centers involved in learning and memory and leads to dementia; drugs   
   inhibiting TRPM2 may break    
   this cycle and help reduce the amyloid burden in the brain."   
      
   The paper was first authored jointly by Drs. Laibaik Park, assistant   
   professor, and Gang Wang, associate research professor, both in the Feil   
   Family Brain and Mind Research Institute.   
      
   Posted October 29, 2014 9:40 AM   
      
      
   http://weill.cornell.edu/news/news/2014/10/blood-vessel-damage-p   
   ays-key-role-in-alzheimers-related-dementia-constantino-iadecola.html   
      
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