Researchers ID the role of an Alzheimer's disease risk gene in the brain

Health News -- December 1, 2022: A recent study links the inflammation that has increasingly been identified as
a significant factor contributing to

Alzheimer's disease to a gene that is concentrated in the brain's cleaning cells, known as microglia. The research may provide a new therapeutic target for the untreatable ailment.

In a joint study published in the November 30 issue of Alzheimer's and Dementia: The Journal of the Alzheimer's Association, scientists from the Grossman School of Medicine at NYU Langone Health and the Icahn School of Medicine at Mount Sinai examined the gene known as inositol polyphosphate-5-phosphatase D (INPP5D).

Immune cells called microglia work as scavengers in the brain to clear out dead cells and amyloid plaques that are linked to the dementia of Alzheimer's disease. Initial research on human genetics connected INPP5D to an increased risk of Alzheimer's disease. Other investigations found higher INPP5D levels in the post-mortem brain tissue of Alzheimer's patients, but the precise function(s) of the gene in both early and late disease, as well as the mechanism causing these changed functions, are still unknown.

In order to "knock down" (switch off) the mouse INPP5D gene in their microglia at the outset of disease, co-senior author Michelle E. Ehrlich, M.D., Professor of Neurology, Pediatrics, and Genetics and Genomic Sciences at Icahn Mount Sinai, employed mice that had been genetically modified to do so. They were able to see the precise effects of the missing gene on brain tissue more clearly because to this method. Then, about three months later, they assessed microglial activity and plaque development. The researchers anticipated that the mice with that gene inactivated would be shielded against the amyloid plaques that are the hallmarks of Alzheimer's disease pathology since INPP5D was known to be high in the brains of Alzheimer's patients.

"When I looked through the microscope, I was quite surprised to see that the mice lacking INPP5D in their microglia had more plaques that mice with normal microglia," said Emilie Castranio, PhD, a postdoctoral fellow in Dr. Ehrlich's lab 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."

"We are encountering unexpected results more and more with modulation of inflammation genes in Alzheimer's," said Dr. Ehrlich. "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."

Dr. Ehrlich realized the need for precise geographic and quantitative gene expression data when it became evident that the INPP5D knockdown shifted microglia about the brain in unexpected ways. With the use of the molecular profiling technique known as spatial transcriptomics, researchers may map the locations of each gene's expression in a tissue sample. Shane Liddelow, PhD, Assistant Professor of Neuroscience, Physiology, and Ophthalmology at NYU Langone, and co-senior author of the new study, a global expert in this strategy, was consulted by Drs. Ehrlich and Castranio.

The findings from spatial transcriptomics highlighted the variety of gene expression variations that microglia might exhibit. Plaque-induced genes are known to be expressed by microglia in the vicinity of amyloid plaques (PIGs). Although the INPP5D knockdown mice replicated the increases in PIGs that had been reported in other studies, the superior technical aspects and geographical transcriptomics analysis allowed for the discovery of additional PIGs. CST7, a gene that encodes the protein cystatin F and is known to be impacted in Alzheimer's and associated with prion diseases, a family of uncommon, progressive neurodegenerative disorders that affect both humans and animals, was the newly identified PIG with the greatest increase in expression in these mice. These results imply that INPP5D and cystatin F should both be taken into account as potential targets for the creation of innovative therapies intended to reduce inflammation in the Alzheimer's brain.

Funding for the study was provided by National Institutes of Health grants P30AG066515, U01AG046170, RF1AG058469, RF1AG059319, R01AG061894, P30AG066514, U01AG046170, RF1AG057440, U01AG046170, and RF1AG057440. Additional funding was provided by the Blas Frangione Foundation, the Neurodegenerative Diseases Consortium from MD Anderson Cancer Center, Alzheimer's Research UK, the Gifford Family Neuroimmune Consortium as part of the Cure Alzheimer's Fund, the Alzheimer's Association, and NYU Langone's Alzheimer's Disease Resource Center. Further funding was provided by Paul Slavik.

Liddelow maintains a financial interest in AstronauTx Ltd., a company investigating possible treatment targets for Alzheimer's disease. The terms and conditions are being managed in accordance with the policies of NYU Langone.

In addition to Drs. Ehrlich and Castranio, other Icahn Mount Sinai investigators in the study were Jean-Vianney Haure-Mirande, PhD; Angie Ramirez, BS; Bin Zhang, PhD; Minghui Wang, PhD, and Sam Gandy, MD, PhD. Other study authors include study co-lead author Philip Hasel, PhD, and Rachel Kim, BA, at NYU Langone, and Charles Glabe, PhD, from the University of California, Irvine.

Story Source:

Materials provided by The Mount Sinai Hospital / Mount Sinai School of Medicine. \Journal Reference:

Emilie L. Castranio, Philip Hasel, Jean‐Vianney Haure‐Mirande, Angie V. Ramirez Jimenez, B. Wade Hamilton, Rachel D. Kim, Charles G. Glabe, Minghui Wang, Bin Zhang, Sam Gandy, Shane A. Liddelow, Michelle E. Ehrlich. Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease. Alzheimer's & Dementia, 2022; DOI: 10.1002/alz.12821

The Mount Sinai Hospital / Mount Sinai School of Medicine. "Researchers identify the role of an Alzheimer's disease risk gene in the brain." ScienceDaily. ScienceDaily, 30 November 2022. .