Gamma-Secretase Linked to Plaques in Both Alzheimer’s and Down Syndrome
Common Thread Between Dementias in Both Diseases
This research was supported by BrightFocus
BrightFocus grantee Huaxi Xu, PhD and colleagues at the Sanford-Burnham Medical Research Institute in La Jolla, CA, have published a paper that sheds light on the origins and connections between the characteristic amyloid plaques found in the brains of individuals with Alzheimer’s disease and the predisposition of individuals with Down syndrome to develop the same plaques, and exhibit Alzheimer’s-type dementia, as they age.
Xu is senior author of the report by Wang et al, published on October 21 in an early, online edition of Cell Reports.
Down syndrome, also known as trisomy 21, is characterized by an extra copy of chromosome 21. The most common chromosome abnormality in humans, it affects about one per 700 U.S. newborns, and is associated with a mild to moderate intellectual disability.
Historically, BrightFocus has funded at least five additional grants looking into similarities between Alzheimer’s and Down syndrome individuals and disease mechanisms.
Both Groups Develop Plaques and Dementias
Life expectancy is increasing for people with Down syndrome. By the age of 40, those individuals almost uniformly exhibit brain changes associated with Alzheimer’s disease. By age 35, approximately 25 percent of people with Down syndrome also have Alzheimer’s-type dementia; by age 65, 75 percent do.
The goal behind the study by Xu et al was to understand how the extra copy of chromosome 21,and the genes on it, might cause individuals with Down syndrome to have a greatly increased risk of developing dementia. They focused on a protein called sorting nexin 27 (SNX27) which 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. In previous mice research, Xu and colleagues had discovered 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.
SNX27 also regulates the generation of beta amyloid—the main component of toxic amyloid plaques. In their latest research, Xu et al have determined that SNX27 reduces beta amyloid generation through interactions with gamma-secretase—a much-studied enzyme that cleaves the biological “raw material” known as amyloid precursor protein (APP) to produce beta amyloid. However, “when SNX27 interacts with gamma-secretase, the enzyme becomes disabled and cannot produce beta amyloid,” explains Xin Wang, PhD, a postdoctoral fellow in Xu’s lab and first author of the report, who was quoted in a news story. Conversely, lower levels of SNX27 lead to increased levels of functional gamma-secretase that in turn lead to increased levels of beta amyloid.
The researchers found that 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. So 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—upping the production of beta amyloid and plaques.
Moving in New Treatment Directions
This complex mechanism also may be affected by other factors, Xu said. However, the main import of the findings, for Alzheimer’s research, is they support inhibiting gamma-secretase as a means to prevent the amyloid plaques found in both Down syndrome and Alzheimer’s.
Xu said their next steps will take them in a potential treatment direction. Working with other labs at Sanford-Burnham, they plan to screen for molecules that can reduce the levels of miRNA-155, and hence restore the level of SNX27. They’ll also look for molecules that can enhance the interaction between SNX27 and gamma-secretase.
He acknowledged BrightFocus’ early grant support behind his lab’s effort, along with support from the National Institutes of Health, the National Natural Science Foundation of China, and other private nonprofit groups.
In the past, Xu has held three BrightFocus grants: one in 2008-11 to fund research into a novel gene that inhibits Alzheimer's amyloid and tau pathology; a 2005-07 effort to use microarray genetic sorting to isolate individual types of neurons in regions of the brain that control cognitive activity and are affected by Alzheimer’s; and a 1999-2001 project, done while Xu was at Rockefeller University, which looked at the interaction between estrogen and beta amyloid production as influenced by gamma-secretase.
Now a faculty member at Sanford-Burnham, Xu directs its Degenerative Disease Program. He also is co-editor-in-chief, along with Guojun Bu, PhD, of Mayo Clinic, of BrightFocus’ official journal, Molecular Neurodegeneration, an open access, peer-reviewed monthly online publication encompassing all aspects of neurodegeneration research at the molecular and cellular levels.
Neurons are the core components of the brain and spinal cord of the central nervous system (CNS) that process and transmit information.
One of the hallmarks of Alzheimer's disease is the accumulation of amyloid plaques between nerve cells (neurons) in the brain. Amyloid is a general term for protein fragments that the body produces normally. Beta amyloid is a protein fragment snipped from an amyloid precursor protein (APP). In a healthy brain, these protein fragments are broken down and eliminated. In Alzheimer's disease, the fragments accumulate to form hard, insoluble plaques.
Amyloid is a general term for protein fragments that the body produces normally. Beta amyloid is a protein fragment snipped from an amyloid precursor protein (APP). In a healthy brain, these protein fragments are broken down and eliminated. In Alzheimer's disease, the fragments accumulate to form hard, insoluble plaques.