The lab of Alison Goate aims to understand the role of microglia in Alzheimer’s disease in the hopes of developing new therapeutics.
Nearly 7 million people in the United States are currently living with Alzheimer’s disease, and as the population continues to age, that number is projected to exceed 13 million by 2060. Several treatments exist that may help relieve some symptoms, but none are able to stop the progression of the disease.
Detrimental changes in the brain that lead to Alzheimer’s are thought to begin some 20 years before telltale symptoms such as memory loss start to appear in patients. Most notably, accumulation of the protein fragment beta-amyloid into clumps, called amyloid plaques, has been linked to the destruction of neurons and other brain cells.
Alison Goate, DPhil, the Jean C. and James W. Crystal Professor of Genomics and Chair of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai, has been studying the genetics of Alzheimer’s disease for nearly four decades. Her work has helped identify disease-causing variants, including the first known mutation to cause familial Alzheimer’s disease. She is the founding director of the Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai, which conducts state-of-the-art research to fuel the development of transformative new drugs and therapeutics.
One area of growing interest in Alzheimer’s research is microglia, a type of immune cell that serves as the clean-up crew of the brain, clearing out cellular debris and dead neurons. Studies in mice have found that microglia switch from a normal to disease-associated state in brain regions affected by amyloid plaques. These disease-associated microglia, or DAM, are characterized by increased expression of genes involved in the clearance of lipid-rich cellular debris.
"Some of the major genes that are upregulated or downregulated in this DAM phenotype are also Alzheimer’s disease risk genes — APOE and TREM2 being perhaps the two most obvious examples," says Goate. "We can see that both genes are important to formation of DAM, and indeed, if you knock out TREM2, we know you can’t make DAM."
In 2013, Goate and her colleagues discovered that rare variants in the gene TREM2 can as much as triple an individual’s risk of developing Alzheimer’s disease. Since TREM2 is predominantly expressed in microglia, the finding has led to a shift in the field regarding the role of microglia in the disease process. In particular, the Goate Lab now focuses specifically on the role of microglia in the genetics of Alzheimer’s.
“If we could find a drug that modifies the way your microglia respond to the amyloid, in a way that protects your brain from neurodegeneration, then such a therapy could be added to existing immunotherapies,” she says.
"That’s the overarching goal, really, of the whole lab and everything that we look at." Earlier this year, a study by the Goate Lab identified two transcription factors — proteins that act as gatekeepers of whether a gene is expressed or not — that regulate the switch from normal microglia to DAM. The researchers knocked out the transcription factors, named BHLHE40/41, from induced pluripotent stem cells and then differentiated them into microglia.
The resulting microglia had increased expression of DAM genes involved in the clearance of harmful cellular debris and toxic cholesterol. When transplanted into the brains of mice with amyloid plaques, they observed an increased population of DAM cells compared to microglia that had both transcription factors intact.
"Now we are in the process of quantifying how having more DAM cells impacts the pathology. Do we have less plaques or maybe we have more compacted plaques?” says Anna Podleśny-Drabiniok, PhD, Instructor in the Department of Genetics and Genomic Sciences and member of the Goate Lab. "The next goal would be to design a small molecule that would degrade BHLHE40/41 in the cell and test the therapeutic angles of such compounds."
The researchers believe that, for reasons unknown, BHLHE40/41 normally stand in the way of other transcription factors that help clean up lipids from the brain. They wish to further explore BHLHE40/41 as possible drug targets for therapeutic modulation of microglial function in Alzheimer’s disease and other disorders of lipid-rich tissues. Podleśny-Drabiniok adds that such a therapy could even benefit patients with other medical conditions, such as obesity, multiple sclerosis, or atherosclerosis. "These DAM cells also appear not only in the brains of Alzheimer’s patients when there are amyloid plaques, but also when there is lipid waste debris," she says. "So in that sense, our findings would be applicable to a broader spectrum of diseases."