Alzheimer’s Disease Researchers Study Gene Associated With the Brain’s Immune Cells

Summary: Reducing the INPP5D gene variant found in brain microglia may help reduce the risk of late-onset Alzheimer’s disease.

Source: Indiana University

Indiana University School of Medicine researchers are studying how reducing a gene variant found in the brain’s immune cells can reduce the risk of late-onset Alzheimer’s disease.

The research team, led by Adrian Oblak, Ph.D., assistant professor of radiology and imaging sciences, and Peter Bor-Chian Lin, Ph.D. candidate in the Medical Neuroscience Graduate Program at the Stark Neuroscience Research Institute, recently published their findings in Alzheimer’s & Dementia.

They focused their investigation on INPP5D, a microglia-specific gene that has been shown to increase the risk of developing late-onset Alzheimer’s disease. Microglia are the immune cells of the brain and there are numerous microglial genes associated with neurodegeneration.

Oblak said the team’s previous data found that elevated levels of INPP5D in laboratory models of Alzheimer’s disease resulted in increased plaque deposition. Knowing this, they aimed to understand how reducing the expression of INPP5D could regulate the pathogenesis of the disease.

Using laboratory models, the researchers reduced gene expression by at least 50%—called haplodeficiency—rather than completely eliminating gene expression to mimic the treatment of pharmacological inhibitors targeting INPP5D as a therapeutic strategy.

Microglia are the immune cells of the brain and there are numerous microglial genes associated with neurodegeneration. The image is in the public domain

“INPP5D deficiency increases amyloid uptake and plaque incorporation in microglia,” Oblak said. “Furthermore, inhibition of the gene regulates microglial functions and attenuates amyloid pathology likely mediated by activation of the TREM2-SYK signaling pathway.”

Absence of the genes also led to preservation of cognitive function in laboratory models. By reducing gene expression in the brain, it created a less neurotoxic environment and improved the movement of microglia – which act as the first line of defense against viruses, toxic materials and damaged neurons – to clear amyloid deposits and plaques.

“These findings suggest that attenuating the function of INPP5D may result in a protective response by reducing the risk of disease and mitigating the effect of amyloid-beta-induced pathogenesis,” said Lin.

About this news about Alzheimer’s disease and genetic research

Author: Press Office
Source: Indiana University
Contact: Press Office – Indiana University
Image: Image is in the public domain

Original Research: Open Access.
“INPP5D Absence Attenuates Amyloid Pathology in a Mouse Model of Alzheimer’s Disease” by Peter Bor‐Chian Lin et al. Alzheimer & Dementia

See also

abstract

INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer’s disease

presentation

Inositol polyphosphate-5-phosphatase (INPP5D) is a lipid phosphatase enriched in microglia in the central nervous system. A non-coding variant (rs35349669) in INPP5D increases the risk for Alzheimer’s disease (AD), and elevated INPP5D expression is associated with increased plaque deposition. INPP5D negatively regulates signaling through several microglial cell surface receptors, including stimulatory receptor expressed on myeloid cells 2 (TREM2); however, the impact of INPP5D inhibition on AD pathology remains unclear.

methods

We used the 5xFAD mouse model of amyloidosis to assess how Inpp5d haplodeficiency regulates amyloid pathogenesis.

Results

Inpp5d haplodeficiency perturbs microglial intracellular signaling pathways that regulate the immune response, including phagocytosis and clearance of amyloid beta (Aβ). It is important to note that Inpp5d haploinsufficiency leads to preservation of cognitive function. Spatial transcriptomic analysis revealed that pathways altered by Inpp5d haploinsufficiency are associated with synaptic regulation and immune cell activation.

Conclusion

These data show that Inpp5d haplodeficiency enhances microglial functions by enhancing plaque clearance and preserves cognitive abilities in 5xFAD mice. Inhibition of INPP5D is a potential therapeutic strategy for AD.