Alzheimer’s Disease – Down Syndrome Research Grants
The Global Down Syndrome Foundation, the Alzheimer’s Association and the Linda Crnic Institute for Down Syndrome are supporting an emerging field of study through a new joint grants initiative called the “New Down Syndrome – Alzheimer’s Disease Investigator Program.” The organizations announced $1.2 million in grants awarded to five scientists to fund groundbreaking research exploring the development of Alzheimer’s disease in individuals with Down syndrome and translate the research into improved treatments for people at risk to develop Alzheimer’s.
Alzheimer’s Disease and Down Syndrome
According to the U.S. Centers for Disease Control, Down syndrome occurs in 1 out of 691 infants in the United States and is caused by three copies of chromosome 21. In addition to early physical and intellectual challenges, individuals with Down syndrome are at a high risk for developing the symptoms characteristic of Alzheimer’s. People with Down syndrome develop the two hallmarks of Alzheimer’s disease – amyloid plaques and tau tangles – in their 30s and 40s. Due to improved clinical care, people with Down syndrome are now regularly living into their sixth decade of life, causing many to develop dementia due to Alzheimer’s.
The high incidence of the symptoms characteristic of Alzheimer’s in people with Down syndrome is thought to be due to the extra copy of chromosome 21, which contains the gene that encodes the amyloid precursor protein (APP). APP is cleaved to form the amyloid-beta peptide; the primary component of plaques. It has been presumed that the extra copy of the gene produces an abnormally high amount of amyloid-beta.
Three grants, each totaling $300,000 for senior investigators:
Sanford-Burnham Medical Research Institute, La Jolla, CA
Roles of miR-155/C/EBPß/SNX27 pathway in Alzheimer’s disease/Down syndrome
People who have Down syndrome develop changes in their brain that resemble those seen in people who have Alzheimer’s disease. These changes are associated with genes on chromosome 21, an extra copy of which occurs in people with Down syndrome. One chromosome 21 gene reduces the levels of the SNX27 protein. This protein is low in the brains of people with Down syndrome. Importantly, mice engineered to have low SNX27 have impaired learning and memory, and this is fixable by restoring SNX27 levels. Dr. Xu’s new studies will determine how SNX27 is involved in Alzheimer’s disease accompanying Down syndrome using mice that have been genetically altered to have Alzheimer’s-like disease. These studies will help reveal how proteins associated with Down syndrome also promote Alzheimer’s-like changes in the brain, and they may help to identify new targets for drugs to prevent or slow disease progression.
Medical University of South Carolina, Charleston, SC
Brain-derived neurotropic factor and executive dysfunction in Down syndrome
People with Down syndrome carry a high risk for Alzheimer’s. Brains of those with Down syndrome have lost some neurons that are needed for important cognitive abilities, which may help explain why individuals with Down syndrome are at a high risk for dementia. Dr. Granholm will perform experiments to clarify the role of neuron damage in people who have both Down syndrome and Alzheimer’s, using a Down syndrome mouse model that overexpresses a gene known to be a cause of Alzheimer’s. The investigators will inject their mice with proteins that receive chemical signals that will alter neurons to reduce or enhance that cell’s ability to transmit chemical messages—enabling scientists to artificially “turn on” or “turn off” cellular activity in the brain. They will then assess how varying activity levels in these neurons affect the production of a hormone-like molecule known to protect brain health and promote memory. People with Alzheimer’s disease and Down syndrome tend to have lower than normal levels of this protein. The researchers will determine whether this treatment rescues the learning and memory deficits in these mice. Results of these efforts could help clarify how various cognitive deficits occur in Down syndrome and Alzheimer’s, and could also lead to novel therapies for people with both conditions.
University of Southern California, Los Angeles, CA
Functional protein interactions in Alzheimer’s disease and Down syndrome
People with Down syndrome have a high risk of developing Alzheimer’s disease, often experiencing Alzheimer’s-related brain changes by age 40. Yet a significant number of individuals with Down syndrome do not develop dementia. How are some people with Down syndrome protected from acquiring Alzheimer’s? One such mechanism could involve a protein called DSCR1, which is located on chromosome 21, along with the gene for amyloid precursor protein (APP). So in Down syndrome there is an extra copy of chromosome 21, giving three copies of the DSCR1 and APP genes, resulting in abnormal production of both of these proteins. Overproduction of APP has been shown to promote the creation of toxic beta-amyloid, an APP fragment that is a key suspect in Alzheimer’s disease, yet it is unclear whether abnormal DSCR1 production may affect Alzheimer’s. To find out, Dr. Chang and colleagues studied the effects of DSCR1 in fruit flies engineered to develop high levels of APP. They found that by increasing brain production of DSCR1, flies were protected against amyloid-related brain cell dysfunction and death. Does DSCR1 protect people with Down syndrome from the brain cell damage characteristic of Alzheimer’s? Dr. Chang will now clarify the mechanism by which DSCR1 protects. They will assess whether increased DSCR1 production protects the functions of axons—the arm-like extensions used to communicate between nerve cells. They will also conduct experiments with cultured mouse neurons to determine whether their findings shed light on Alzheimer’s in mammals. Ultimately, Dr. Chang’s study could shed new light on the molecular links between Down syndrome and Alzheimer’s disease. It could also point toward novel therapies for both disorders.
Two grants, each totaling $150,000 for new investigators:
University of Kentucky Research Foundation, Lexington, KY
Inflammatory biomarkers to predict transition to dementia in Down syndrome
While still in their fourth decade of life, nearly all people who have Down syndrome will begin to develop brain changes associated with Alzheimer’s disease, although brain function does not begin to decline until later. Interestingly, Down syndrome is associated with increased levels of proteins that promote inflammation, which has been implicated in the development and progression of Alzheimer’s. Donna M. Wilcock and colleagues have been studying biomarkers of brain inflammation and how they relate to the development of Alzheimer’s. They will measure molecules in the blood of study participants with Down syndrome to determine if these levels change at the onset of Alzheimer’s. They will determine whether the blood changes correlate with changes in the brain determined by imaging. These studies may help to identify biomarkers in blood indicating the presence of brain inflammation associated with the onset of Alzheimer’s in people with Down syndrome.
Bar-Ilan University, Ramat-Gan, Israel
Developing a DNA vaccine for Alzheimer’s disease in people with Down syndrome
People who have Down syndrome have a high risk of developing Alzheimer’s disease, which begins to develop when they are still in their 30s and 40s. Clinical trials have attempted to find a vaccine to slow or prevent Alzheimer’s disease, but to date there is no treatment to stop or slow disease progression. Most vaccines have been designed to use the immune system to remove beta-amyloid, which is a protein fragment that is toxic to nerve cells and forms amyloid plaques, one of the characteristic features of Alzheimer’s. Eitan Okun and colleagues are working to develop a new type of vaccine for Alzheimer’s, including people who have Down syndrome. They will modify a virus so it produces a short version of beta-amyloid, which hopefully will stimulate the immune system to remove beta-amyloid with less chance of side effects. Once an optimal vaccine is developed, the researchers will study its ability to remove beta-amyloid from mice that have a condition resembling Down syndrome and Alzheimer’s. The researchers will also test the mice to determine if the vaccine restores memory. These studies may advance the development of a new type of vaccine to slow or prevent the progression of Alzheimer’s disease, including Alzheimer’s in people who have Down syndrome.