A collaborative research effort by the Icahn School of Medicine at Mount Sinai and the Grossman School of Medicine at NYU Langone Health has further linked a gene concentrated in microglia as a mechanism to the inflammation in the brain, which is a key factor in the development of Alzheimer’s disease (AD). Study results were published in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association.
Microglia are immune cells located in the brain that remove the dead cells and amyloid plaques that are associated with AD. For this study, the team focused on the gene INPP5D (inositol polyphosphate-5-phosphatase D) which previous studies have linked as a risk to AD development. While other studies have revealed elevated levels of INPP5D in the post mortem brain tissues of people who suffered from AD the activity of the gene and its role in the development of both early- and late-stage AD has remained unknown.
INPP5D is concentrated in the microglia, so to develop a better understanding of its role in AD, co-senior author Michelle E. Ehrlich, MD, professor of Neurology, Pediatrics, and Genetics and Genomic Sciences at Icahn Mount Sinai used mouse models with the INPP5E gene knocked down in the microglia at the onset of AD pathology. This allowed the research team to observe the effect on the brain in the absence of the gene.
After three months, the investigators measure the amount of amyloid plaque buildup and the activity of the microglia. Because of the prior findings of elevated levels of INP5D in post mortem tissues noted in previous studies, the researchers anticipated that the mice with the knocked down gene would be protected from the accumulation of amyloid plaques which cause AD.
But that was not the case.
“When I looked through the microscope, I was quite surprised to see that the mice lacking INPP5D in their microglia had more plaques than mice with normal microglia,” said Emilie Castranio, PhD, a postdoctoral fellow in the Ehrlich lab at Mt. Sinai and co-first author on the new paper. “Microglia frequently sit on the edges of the plaques but when INPP5D was knocked down, the plaques were completely covered with them.”
Added Erlich: “We are encountering unexpected results more and more with modulation of inflammation genes in Alzheimer’s. At this point in our understanding, we still do not know which of these genes to target for therapeutic intervention in humans, or whether to turn them up or turn them off depending on disease stage. Because these experiments are not possible in living humans, we rely on mouse models to show us the way. We also use these mice to help us predict whether a particular gene is more related to disease onset or disease progression, with the caveat that mouse and human microglia differ in important ways. Despite these differences, the plaque-associated gene signature we identified overlaps with human Alzheimer’s disease gene networks.”
Based on the unexpected findings in the INPP5D mice, Erlich and team turned to spatial transcriptomics to help them discover more detailed quantitative and spatial gene expression in these models. This method illuminated the range of gene expression changes that can occur I the microglia. Microglia near amyloid plaques are known to express genes designated as plaque-induced genes (PIGs). The team showed that not only did the INPP5D knockdown mice replicate PIGs that have been described in previous research, but the spatial transcriptomics also revealed additional PIGs. Of the newly identified PIGs, one called CST7 showed the greatest increase. CST7 a gene encoding the protein cystatin F that is known to be impacted in Alzheimer’s and associated with prion diseases, a family of rare, progressive neurodegenerative disorders that affect both humans and animals.
Based on these findings, the researchers note that both INPP5D and cystatin F should be considered as promising targets for development of novel interventions aimed at mitigating inflammation in the Alzheimer’s brain.