July 25, 2013
Researchers Explore Genetic Interactions In The Alzheimer’s Brain
Rebekah Eliason for redOrbit.com - Your Universe Online
Researchers at Columbia University Medical Center recently discovered key molecular pathways in the brain that lead to late-onset Alzheimer's disease, the most common form of the disorder. Both systems biology and cell biology tools were used in this new study that presents a unique approach to Alzheimer's disease research as well as new possibilities for drug targets.
Most Alzheimer research is based on laboratory studies of people with the rare, early onset inherited or familial type of the disease. Asa Abeliovich, MD, PhD, associate professor of pathology and cell biology and of neurology at Columbia, said, "Such studies have provided important clues as to the underlying disease process, but it's unclear how these rare familial forms of Alzheimer's relate to the common form of the disease. Most important, dozens of drugs that 'work' in mouse models of familial disease have ultimately failed when tested in patients with late-onset Alzheimer's. This has driven us, and other laboratories, to pursue mechanisms of the common form of the disease."
A combination of genetic and environmental factors make non-familial Alzheimer's complex, with each factor having its own unique effect on the development and progression of the disease. Genome-wide association studies have been able to identify a common set of genes that indicate increased risk for developing Alzheimer's. Previously, a key research objective was to understand how common genetic factors work to impact the probability of developing Alzheimer's.
Researchers in this current study discovered several key pathways that link genetic risk factors for Alzheimer's together. By combining biology and cell biology tools, researchers studied a computational analysis of network changes in the expression of genes in the brain tissue of individuals at risk for developing Alzheimer's.
The specific genetic factor focused on in this study is one of the most significant genetic factors known as APOE4 and is found in one third of people with Alzheimer's. Those who have one copy of APOE4 are three times as likely to contract late-onset Alzheimer's, while people with two copies are ten times as likely.
Dr. Albeliovich said, "In this study we initially asked: If we look at autopsy brain tissue from individuals at high risk for Alzheimer's, is there a consistent pattern? Surprisingly, even in the absence of Alzheimer's disease, brain tissue from individuals at high risk (who carried APOE4 in their genes) harbored certain changes reminiscent of those seen in full-blown Alzheimer's disease. We therefore focused on trying to understand these changes, which seem to put people at risk. The brain changes we considered were based on 'transcriptomics' - a broad molecular survey of the expression levels of the thousands of genes expressed in brain."
Using the same biological tools, researchers discovered a dozen candidates for genes acting as a master regulator that link APOE4 to the destructive events in the brain which all lead to Alzheimer's dementia. Successive studies have shown several of the candidate genes are involved in the transport and processing of amyloid precursor protein (APP) occurring in neurons. This APP produces amyloid beta which is the protein that builds up in the brain cells of people with Alzheimer's. Researchers were able to link together genetic factors, APOE4 and the disease pathology.
Among the candidate genetic factors evaluated, two more genes, SV2A and RFN219, were analyzed as well. "We were particularly interested in SV2A, as it is the target of a commonly used anti-epileptic drug, levetiracetam. This suggested a therapeutic strategy. But more research is needed before we can develop clinical trials of levetiracetam for patients with signs of late-onset Alzheimer's disease."
By using human-induced neurons carrying the APOE4 genetic variant, researchers were able to evaluate the role of SV2A. When the neurons were treated with levetiracetam, which inhibits SV2A, there was a reduction in the amount of amyloid beta produced. It was also shown in this study RFN219 affects the APP-processing in brain cells carrying the APOE4 genetic variant.
"Our findings suggest that both SV2A and RFN219 are candidate drug targets," said Dr. Abeliovich. "What's exciting to us is that these approaches may play a role in the development of drugs for the common non-familial form of Alzheimer's disease. This has been an enormous challenge."
The team's study was published July 24, 2013 in the journal Nature. Contributors, who were members of the CUMC's Taub Institute for Research on Alzheimer's Disease and the Aging Brain included Herve Rhinn, Ryousuke Fujita, Liang Qiang, Rong Chen, and Joseph H. Lee. Dr. Lee is also a member of CUMC's Gertrude H. Sergievsky Center.
This research was supported by grants from the National Institutes of Health.