Role of genes associated with identified Alzheimer’s disease risk genes

A collaborative research effort by Icahn School of Medicine, Mount Sinai and Grossman School of Medicine, NYU Langone Health further implicated genes that are concentrated in microglia as mechanisms of brain inflammation. Alzheimer’s disease (advertisement). Research results announced of Alzheimer’s Disease and Dementia: Journal of Alzheimer’s Disease.

Microglia are immune cells in the brain that clear dead cells and amyloid plaques associated with AD. For this study, the team focused on the gene INPP5D (inositol polyphosphate-5-phosphatase D), which has been implicated in previous studies as a risk factor for developing Alzheimer’s disease. Other studies have revealed elevated levels of INPP5D in postmortem brain tissue of people with Alzheimer’s disease, but the gene’s activity and its role in the development of both early and late Alzheimer’s disease remain unclear.

Because INPP5D is concentrated in microglia, to better understand its role in Alzheimer’s disease, co-lead author Michelle E. Ehrlich, MD reported that the INPP5E gene was knocked down in microglia during the onset of AD pathology. This allowed the research team to observe the effects on the brain when the gene was absent.

After three months, researchers measure the amount of amyloid plaque buildup and microglial activity. Previous findings of elevated INP5D levels in postmortem tissue pointed out in previous studies led the researchers to expect that mice carrying the knocked-down gene would be protected from the accumulation of amyloid plaques that cause AD.

But it wasn’t.

“When we looked under the microscope, we were very surprised to find that mice without INPP5D in their microglia had more plaques than mice with normal microglia,” said co-first author of the new paper. “Microglia often sit at the edges of plaques, but when INPP5D is knocked down, plaques are completely covered by them.”

Erlich added: At this point in our understanding, it is not yet known which of these genes will be targeted for therapeutic intervention in humans, or whether to turn them on or off depending on the stage of the disease. Since these experiments are not possible in living humans, we rely on mouse models to show the way. We can also use these mice to predict whether certain genes are associated with disease development or progression, although we note that mouse and human microglia differ in important ways. please give me. Despite these differences, the plaque-associated gene signatures we identified overlap with the human Alzheimer’s disease gene network. ”

Based on the unexpected findings in INPP5D mice, Erlich and team turned to spatial transcriptomics to help discover more detailed quantitative and spatial gene expression in these models. This method revealed a range of possible gene expression changes in microglia. Microglia near amyloid plaques are known to express genes called plaque-inducible genes (PIGs). The team showed that INPP5D-knockdown mice not only duplicated the PIG described in previous studies, but spatial transcriptomics also revealed an additional his PIG. Of the newly identified PIGs, one called CST7 showed the largest increase. The gene encoding the CST7 protein cystatin F, known to affect Alzheimer’s disease and is associated with prion diseases, a family of rare and progressive neurodegenerative diseases that affect both humans and animals. I’m here.

Based on these findings, researchers suggest that both INPP5D and Cystatin F should be considered promising targets for the development of new interventions aimed at reducing brain inflammation in Alzheimer’s disease. said.