A team of investigators from Case Western Reserve School of Medicine, say they have identified a gene and associated protein that previously had not been associated with Alzheimer’s disease (AD), which could potentially be suppressed to slow the progression of Alzheimer’s disease.
The research was published this month by the journal Nature Communications, and supported by grants from the National Institutes of Health (NIH) and the Alzheimer’s Association.
For the research led by Xinglong Wang, an associate professor of pathology at the School of Medicine, the team correlated roughly 1 million single nucleotide polymorphisms (SNPs) with brain images obtained from the Alzheimer’s Disease Neuroimaging Initiative, an NIH-supported project. Using this method, a specific SNP in the FAM222 gene was identified that was linked to a variety of different patterns of regional brain atrophy.
Upon further investigation, the investigators found evidence that the protein encoded by the gene FAM222A is associated with AD patient-related beta-amyloid plaques, regional brain atrophy, and the protein the team dubbed ‘aggregatin’—which attaches to amyloid beta peptide and accumulates in the center of plaque in AD patients.
“Based on the data we have, this protein can be an unrecognized new risk factor for Alzheimer’s disease (AD),” said Xinglong Wang, an associate professor of pathology at the School of Medicine in a press release. “We also see this as a potential novel therapeutic target for this devastating disease.”
Wang noted that additional research would be required to confirm the function and role aggregatin plays in the development of AD, he is optimistic this discovery could one day lead to clinical trials of targeting the protein. With an eye toward this possibility, Wang, his colleague Xiaofeng Zhu, a professor of Population and Quantitative Health Sciences at the School of Medicine and the research team have filed for a patent via Case Western’s Office of Research and Technology Management for “novel Alzheimer’s disease treatments and diagnosis based on this and related study.”
After identifying aggregatin, the research team then injected mouse models with the protein it had made from the FAM222A gene. They discovered that plaque (amyloid deposits) formation accelerated in the brain of the mice injected with aggregatin, resulting in more neuroinflammation and cognitive dysfunction due to the protein binding directly to the amyloid beta peptide, which facilitated aggregation and plaque formation.
Conversely, when the protein was suppressed plaques were reduced and neuroinflammation and cognitive impairment alleviated. Their findings indicate that reducing levels of this protein and inhibition of its interaction with amyloid beta peptide could potentially be therapeutic—not necessarily to prevent Alzheimer’s but to slow its progression.
“We’re very excited about this because our study is likely the first systematic work combining the identification from a genome-wide association study of high dimensional brain-imaging data and experimental validation so perfectly in Alzheimer’s disease,” Zhu said.