Abstract
Researchers at the Icahn School of Medicine at Mount Sinai recently published results in Nature Neuroscience that could change how scientists view Alzheimer’s and lead to novel therapeutic targets for the disease. The international, genome-wide association study, which analyzed genomes from 14,406 Alzheimer’s patients and 25,849 disease-free controls, revealed that myeloid cells express a network of genes associated with Alzheimer’s disease risk.
While these results did not surprise the study’s principal author, Alison Goate, Ph.D., professor of neuroscience and director of The Ronald M. Loeb Center for Alzheimer’s Disease at Mount Sinai, she confessed that their earlier work leading up to the study did: “What surprised me four years ago was that when we took these brain homogenate we couldn’t find any evidence of there being gene-expression changes in brain tissue that mapped to the same polymorphisms that were affecting Alzheimer’s disease risk. For a brain disease that seems really weird, right? You think, well surely, you’ve got to be able to detect it in brain tissue if it’s a brain disease.”
Trifonenko / Getty Images
Only after co-author Towfique Raj, Ph.D., and colleagues published a study in Science linking Alzheimer’s risk genes to monocytes did the researchers turn their focus to immune cells—using monocytes and macrophages isolated from the blood as a proxy for microglia, which account for approximately 5% of cells in a normal brain. Although microglia—myeloid cells that function as the brain’s immune surveillance system—are known to accumulate around amyloid plaques, it was previously considered a consequence of the disease rather than a contributing factor.
By mapping the expression of Alzheimer’s disease risk genes, regulated by the transcription factor PU.1 and its encoding gene SPI1, to myeloid cells, researchers have ascribed a much greater role to microglial function, and they hypothesize that lower levels of PU.1/SPI1, which correlated with a later age of disease onset, offer protection from Alzheimer’s by tipping the balance between neuroprotective and neurotoxic microglial function.
While PU.1 itself may not provide a suitable therapeutic target, both because of its location in the cell nucleus and its far-reaching role in regulating the function of many different genes, it could point researchers towards more accessible cell-surface proteins important to microglial function.
“Alzheimer’s disease is becoming more common as our population ages,” concluded Dr. Goate, “and, among the top ten killers in this country, it’s the only one that’s increasing in prevalence and the only one that doesn’t have any kind of [effective] treatment.”