From: drarwingnuttephd@gmail.com   
      
   New insight on why people with Down syndrome invariably develop Alzheimer's   
   disease   
      
   Amyloid plaques are found in the brains of people with Down syndrome and   
   Alzheimer's disease. Credit: Juan Gartner   
      
   A new study by researchers at Sanford-Burnham Medical Research Institute   
   reveals the process that leads to changes in the brains of individuals with   
   Down syndrome--the same changes that cause dementia in Alzheimer's patients.   
   The findings, published in    
   Cell Reports, have important implications for the development of treatments   
   that can prevent damage in neuronal connectivity and brain function in Down   
   syndrome and other neurodevelopmental and neurodegenerative conditions,   
   including Alzheimer's disease.   
      
   Down syndrome is characterized by an extra copy of chromosome 21 and is the   
   most common chromosome abnormality in humans. It occurs in about one per 700   
   babies in the United States, and is associated with a mild to moderate   
   intellectual disability. Down    
   syndrome is also associated with an increased risk of developing Alzheimer's   
   disease. By the age of 40, nearly 100 percent of all individuals with Down   
   syndrome develop the changes in the brain associated with Alzheimer's disease,   
   and approximately 25    
   percent of people with Down syndrome show signs of Alzheimer's-type dementia   
   by the age of 35, and 75 percent by age 65. As the life expectancy for people   
   with Down syndrome has increased dramatically in recent years--from 25 in 1983   
   to 60 today--   
   research aimed to understand the cause of conditions that affect their quality   
   of life are essential.   
      
   "Our goal is to understand how the extra copy of chromosome 21 and its genes   
   cause individuals with Down syndrome to have a greatly increased risk of   
   developing dementia," said Huaxi Hu, Ph.D., professor in the Degenerative   
   Diseases Program at Sanford-   
   Burnham and senior author of the paper. "Our new study reveals how a protein   
   called sorting nexin 27 (SNX27) regulates the generation of beta-amyloid--the   
   main component of the detrimental amyloid plaques found in the brains of   
   people with Down syndrome    
   and Alzheimer's. The findings are important because they explain how   
   beta-amyloid levels are managed in these individuals."   
      
   Beta-Amyloid, Plaques and Dementia   
   Xu's team found that SNX27 regulates beta-amyloid generation. Beta-amyloid is   
   a sticky protein that's toxic to neurons. The combination of beta-amyloid and   
   dead neurons form clumps in the brain called plaques. Brain plaques are a   
   pathological hallmark of    
   Alzheimer's disease and are implicated in the cause of the symptoms of   
   dementia.   
      
   "We found that SNX27 reduces beta-amyloid generation through interactions with   
   gamma-secretase--an enzyme that cleaves the beta-amyloid precursor protein to   
   produce beta-amyloid," said Xin Wang, Ph.D., a postdoctoral fellow in Xu's lab   
   and first author    
   of the publication. "When SNX27 interacts with gamma-secretase, the enzyme   
   becomes disabled and cannot produce beta-amyloid. Lower levels of SNX27 lead   
   to increased levels of functional gamma-secretase that in turn lead to   
   increased levels of beta-   
   amyloid.   
   "   
   SNX27's Role in Brain Function   
   Previously, Xu and colleagues found that SNX27 deficient mice shared some   
   characteristics with Down syndrome, and that humans with Down syndrome have   
   significantly lower levels of SNX27. In the brain, SNX27 maintains certain   
   receptors on the cell surface-   
   -receptors that are necessary for neurons to fire properly. When levels of   
   SNX27 are reduced, neuron activity is impaired, causing problems with learning   
   and memory. Importantly, the research team found that by adding new copies of   
   the SNX27 gene to the    
   brains of Down syndrome mice, they could repair the memory deficit in the mice.   
      
   The researchers went on to reveal how lower levels of SNX27 in Down syndrome   
   are the result of an extra copy of an RNA molecule encoded by chromosome 21   
   called miRNA-155. miRNA-155 is a small piece of genetic material that doesn't   
   code for protein, but    
   instead influences the production of SNX27.   
      
   With the current study, researchers can piece the entire process together--the   
   extra copy of chromosome 21 causes elevated levels of miRNA-155 that in turn   
   lead to reduced levels of SNX27. Reduced levels of SNX27 lead to an increase   
   in the amount of    
   active gamma-secretase causing an increase in the production of beta-amyloid   
   and the plaques observed in affected individuals.   
      
   "We have defined a rather complex mechanism that explains how SNX27 levels   
   indirectly lead to beta-amyloid," said Xu. "While there may be many factors   
   that contribute to Alzheimer's characteristics in Down syndrome, our study   
   supports an approach of    
   inhibiting gamma-secretase as a means to prevent the amyloid plaques in the   
   brain found in Down syndrome and Alzheimer's."   
      
   "Our next step is to develop and implement a screening test to identify   
   molecules that can reduce the levels of miRNA-155 and hence restore the level   
   of SNX27, and find molecules that can enhance the interaction between SNX27   
   and gamma-secretase. We are    
   working with the Conrad Prebys Center for Chemical Genomics at Sanford-Burnham   
   to achieve this," added Xu.   
      
      
       
   Explore further: Contributions of a 'sorting nexin' protein to learning   
   impairments in Down's syndrome   
   Journal reference: Cell Reports     
   Provided by Sanford-Burnham Medical Research Institute    
      
      
   http://medicalxpress.com/news/2014-10-insight-people-syndrome-in   
   ariably-alzheimer.html   
      
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