Summary: Reduction of the INPP5D gene variant found in the brain’s microglia could help to diminish the risk of late-onset Alzheimer’s disease.
Source: Indiana University
Indiana University School of Medicine researchers are studying how the reduction of a gene variant found in the brain’s immune cells could diminish 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, a Ph.D. candidate in the Medical Neuroscience Graduate Program at Stark Neurosciences 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 for developing late-onset Alzheimer’s disease. Microglia are the brain’s immune cells and there are multiple microglial genes associated with neurodegeneration.
Oblak said the team’s previous data revealed that elevated levels of INPP5D in Alzheimer’s disease lab models resulted in increased plaque deposition. Knowing this, they aimed to understand how reducing expression of INPP5D might regulate disease pathogenesis.
Using models in the lab, the researchers reduced the expression of the gene by at least 50%—called haplodeficiency—rather than completely knocking out the expression of the gene to mimic the treatment of pharmacological inhibitors targeting INPP5D as therapeutic strategies.
“INPP5D deficiency increases amyloid uptake and plaque engagement in microglia,” Oblak said. “Furthermore, inhibiting the gene regulates microglial functions and mitigates amyloid pathology that are likely mediated by TREM2-SYK signaling pathway activation.”
The gene deficiency also led to the preservation of cognitive function in the lab models. By reducing the expression of the gene 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 mitigating the function of INPP5D can result in a protective response by diminishing disease risk and mitigating the effect of amyloid beta induced pathogenesis,” Lin said.
About this Alzheimer’s disease and genetics research news
INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer’s disease
Inositol polyphosphate-5-phosphatase (INPP5D) is a microglia-enriched lipid phosphatase 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 via several microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2); however, the impact of INPP5D inhibition on AD pathology remains unclear.
We used the 5xFAD mouse model of amyloidosis to assess how Inpp5d haplodeficiency regulates amyloid pathogenesis.
Inpp5d haplodeficiency perturbs the microglial intracellular signaling pathways regulating the immune response, including phagocytosis and clearing of amyloid beta (Aβ). It is important to note that Inpp5d haploinsufficiency leads to the preservation of cognitive function. Spatial transcriptomic analysis revealed that pathways altered by Inpp5d haploinsufficiency are related to synaptic regulation and immune cell activation.
These data demonstrate that Inpp5d haplodeficiency enhances microglial functions by increasing plaque clearance and preserves cognitive abilities in 5xFAD mice. Inhibition of INPP5D is a potential therapeutic strategy for AD.