Enlisting genes and the immune system to fight Alzheimer’s

The amyloid plaques that characterize Alzheimer’s disease are surrounded by microglia, which are neurological cells that help govern how the brain responds to injury. Now, scientists at the University of Pennsylvania have discovered three genetic variants in microglia that may enhance the immune system’s ability to fight Alzheimer’s—and that may be targetable with drugs.

The genetic variants, called PLCG2, ABI3 and TREM2, produce proteins that are abundant in microglia, according to a press release from the university. They were discovered by analyzing DNA from 85,000 patients who are included in the International Genomics of Alzheimer's Project, a multinational effort to map genes associated with the disease. The research was published in the journal Nature Genetics.

The researchers set out to show that PLCG2, ABI3, and TREM2 are part of an immune protein network that influences the risk of developing Alzheimer’s—meaning they don’t just appear as part of the brain’s response to damage brought on by the disease. They proved that hunch in three stages of research. First they sequenced all of the protein-coding regions from 34,290 patient samples. In the next two stages, they whittled down sequences of variants, verifying their findings against other samples taken from Alzheimer’s patients.

One of the genes implicated, PLCG2, produces an enzyme that stands out as a potential drug target. But the scientists still need to figure out how best to target genetic changes in the microglia. Among the questions still to be answered: Should the injury response be inhibited or boosted? And at what stage of the disease should these genetic variants be targeted?

"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, in the release.

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The scientific community has long been interested in targeting microglia to treat Alzheimer’s. Last year, scientists at the University of California in Irvine used the experimental cancer drug pexidartinib to flush out excessive microglia in the brains of mouse models of Alzheimer’s. They noted improved memory and cognition in the animals. Researchers at the Cleveland Clinic have found that the experimental drug NTRX-07 triggers a beneficial anti-inflammatory response in microglial cells when tested in mice.

Even though the exact cause of Alzheimer’s is still a matter of intense debate, the research community remains focused on combating amyloid plaques in the brain. In May, a team of researchers backed by the NIH described a genetic mutation called the Met allele, which they showed contributes to a decline in memory and cognitive skills in Alzheimer’s patients with high beta-amyloid levels. Pfizer and Akili are working on developing noninvasive technologies for detecting amyloid in the brain.

The ADGC at Penn is supported by the NIH’s National Institute on Aging and is one of four consortia involved in the International Genomics of Alzheimer's Project. The researchers involved in the project are collecting and sharing genetic data in the hopes of accelerating progress in treating Alzheimer’s.

“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."