University of Pennsylvania researchers report three genetic variants in microglia that could be drug targets for enhancing the immune system against Alzheimer’s Disease.
According to the Alzheimer’s Association, more than 5 million Americans are currently living with Alzheimer’s Disease and that number could reach 16 million by 2050. More than two-thirds of sufferers are women, and 1 in 10 people aged 65 and older have the disease. Alzheimer’s is the 6th leading cause of death in the US and kills more people than breast and prostate cancers combined.
Researchers at the University of Pennsylvania believe they have identified new targets for the development of drugs that could enlist the aid of the immune system in preventing Alzheimer’s Disease. There is significant debate over the cause of Alzheimer’s Disease, but most research focuses on the amyloid plaques that develop in the brain. These plaques are surrounded by neurological cells called microglia that help determine how the brain responds to injury. Previous research has shown that microglia play some role in Alzheimer’s disease. The scientists at the University of Pennsylvania have identified three different genetic variants (PLCG2, ABI3 and TREM2) of these microglia that could be targets for Alzheimer’s drugs.
The variants were identified after evaluating the DNA from 85,000 patients participating in the International Genomics of Alzheimer's Project, which is a worldwide program with the goal of mapping the genes involved in Alzheimer’s Diseases. The variants produce proteins that are present in microglia at high levels and were shown by the researchers to influence the risk of developing Alzheimer’s. The work involved sequencing the protein-coding regions from 34,290 patient samples.
The next challenge for the scientists is to determine how to target genetic changes in the microglia, at what stage of the diseases the variants should be targeted and whether the injury response should be increased or limited.
"Since prevention is a key goal of therapy, influencing microglial cells before onset of cognitive changes needs to be explored," said Gerard Schellenberg, Ph.D., a Professor and Director of the Alzheimer Disease Genetics Consortium (ADGC) at the University of Pennsylvania. “These multiple gene 'hits' all originating from microglia,” Schellenberg said of Penn’s most recent discovery, “are the clearest demonstration that these cells are part of Alzheimer's pathology and, more importantly, provide clear protein targets where we can start to intervene with drugs."