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Home | Pregnancy Timeline | News Alerts |News Archive Oct 30, 2014

Amyloid plaques are found in the brains of people with Down syndrome and Alzheimer's disease.
Image Credit: Juan Gartner

 







CDC Growth Standards 0 to 2 Years of Age



 

 

Down syndrome develops into Alzheimer's

The process that leads to brain structure changes in individuals with Down's, is the same that causes dementia in Alzheimer's patients. Understanding the steps involved in this process may lead to treatments for these conditions.

The findings, published in Cell Reports, have important implications for treatments that can prevent damage in neural connectivity and brain function in Down syndrome and other neurodevelopmental and neurodegenerative conditions, including Alzheimer's.

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. But it is also associated with an increased risk for developing Alzheimer's disease.


By age 40, nearly 100 percent of all individuals with Down syndrome develop changes in the brain associated with Alzheimer's disease. Approximately 25 percent show signs of Alzheimer's-type dementia by age 35, and 75 percent by age 65.

As the life expectancy for people with Down syndrome has increased dramatically in recent years — from 25 years of age in 1983 to 60 years today — research aims to understand and improve their quality of life.


"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.

"Our new study reveals how a protein called sorting nexin 27 (SNX27) regulates generation of beta-amyloid — the main component in the detrimental amyloid plaques found in brains of people with Down syndrome and Alzheimer's. These findings are important because they explain how beta-amyloid levels are managed in Down's individuals."
  explains Huaxi Xu, Ph.D., professor, Degenerative Diseases Program at Sanford-Burnham Medical Research Institute, and senior author.


Xu's team found that SNX27 regulates beta-amyloid generation. Beta-amyloid is a sticky protein that's toxic to neurons as it binds Beta-amyloid to dead neurons, forming clumps in the brain called plaques. Brain plaques are a pathological hallmark of Alzheimer's disease and are implicated in symptoms of dementia.


"We found that SNX27 reduces beta-amyloid generation through interaction with gamma-secretase — an enzyme that splits 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 leads to increased levels of beta-amyloid."

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 its' cell surface — receptors that are needed for neurons to fire properly.


When levels of SNX27 are reduced, neuron activity is impaired, causing problems with learning and memory.

However, the research team found that adding new copies of the SNX27 gene to the brains of Down syndrome mice, they could repair memory deficits 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. Although the miRNA-155 molecule is a small piece of genetic material, it doesn't code for protein but instead influences the amount of SNX27 produced.


The current study has pieced together the entire plaque process — an extra copy of chromosome 21 causes elevated levels of miRNA-155 which leads to reduced levels of SNX27.

A reduction in SNX27 levels leads to an increase in active gamma-secretase causing an increase in the production of beta-amyloid and thus an increase in the plaques observed in Down syndrome 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 the approach of inhibiting gamma-secretase 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. As well as 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."

Huaxi Xu, Ph.D., professor in the Degenerative Diseases Program at Sanford-Burnham Medical Research Institute, and senior author of the paper.


Article Highlights
•SNX27 regulates γ-secretase cleavage of APP and consequent Aβ generation
•SNX27 binds to presenilin 1 and regulates γ-secretase complex formation and activity
•Transduction of SNX27 reduces Aβ in an AD mouse model
•Snx27 deletion promotes Aβ generation and neuronal loss in an AD mouse model

Summary
Patients with Down syndrome (DS) invariably develop Alzheimer’s disease (AD) pathology in their 40s. We have recently found that overexpression of a chromosome 21-encoded microRNA-155 results in decreased levels of the membrane trafficking component, SNX27, diminishing glutamate receptor recycling and thereby impairing synaptic functions in DS. Here, we report a function of SNX27 in regulating β-amyloid (Aβ) generation by modulating γ-secretase activity. Downregulation of SNX27 using RNAi increased Aβ production, whereas overexpression of full-length SNX27, but not SNX27ΔPDZ, reversed the RNAi-mediated Aβ elevation. Moreover, genetic deletion of Snx27 promoted Aβ production and neuronal loss, whereas overexpression of SNX27 using an adeno-associated viral (AAV) vector reduced hippocampal Aβ levels in a transgenic AD mouse model. SNX27 associates with the γ-secretase complex subunit presenilin 1; this interaction dissociates the γ-secretase complex, thus decreasing its proteolytic activity. Our study establishes a molecular mechanism for Aβ-dependent pathogenesis in both DS and AD.

This research was supported in part by US NIH/National Cancer Institute Grant AG038710, AG021173, NS046673, AG030197 and AG044420, and grants from the Alzheimer's Association, the Global Down Syndrome Foundation, the American Health Assistance Foundation and the National Natural Science Foundation of China.

About Sanford-Burnham Medical Research Institute
Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-Burnham takes a collaborative approach to medical research with major programs in cancer, neurodegeneration and stem cells, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is recognized for its National Cancer Institute-designated Cancer Center, its NIH-designated Neuroscience Center Cores, and expertise in drug discovery technologies. Sanford-Burnham is a nonprofit, independent institute that employs more than 1,000 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at sanfordburnham.org.

Sanford-Burnham can also be found on Facebook at facebook.com/sanfordburnham and on Twitter @sanfordburnham.

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