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Published on: March 16, 2016
INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease
Peter Bor-Chian Lin1, Andy Po-Yi Tsai1, Disha Soni1
1Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Introduction:
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.
Methods:
We used the 5xFAD mouse model of amyloidosis to assess how Inpp5d haplodeficiency regulates amyloid pathogenesis.
Results:
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.
Conclusion:
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.
Insights
Inhibiting Inositol polyphosphate-5-phosphatase (INPP5D) enhances microglial function, improving amyloid plaque clearance and preserving cognitive abilities in Alzheimer's disease (AD) mouse models. This suggests INPP5D inhibition as a potential AD therapy.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Inositol polyphosphate-5-phosphatase (INPP5D) is a microglia-specific enzyme in the central nervous system.
- A genetic variant of INPP5D is linked to increased Alzheimer's disease (AD) risk, with higher INPP5D levels correlating with greater amyloid plaque deposition.
- INPP5D modulates signaling through microglial receptors like TREM2, but its precise role in AD pathogenesis requires further investigation.
Purpose of the Study:
- To investigate the effects of Inpp5d inhibition on amyloid pathogenesis in a mouse model of AD.
- To determine if reducing Inpp5d levels impacts microglial function and cognitive outcomes in the context of amyloidosis.
Main Methods:
- Utilized the 5xFAD transgenic mouse model, which develops amyloidosis.
- Assessed the impact of Inpp5d gene haplodeficiency on amyloid plaque deposition and associated pathology.
- Employed spatial transcriptomic analysis to identify molecular pathways affected by Inpp5d haploinsufficiency.
Main Results:
- Inpp5d haplodeficiency altered microglial intracellular signaling pathways involved in immune response, including phagocytosis and amyloid-beta (Aβ) clearance.
- Mice with Inpp5d haploinsufficiency showed preserved cognitive function.
- Spatial transcriptomics revealed that Inpp5d haploinsufficiency impacts pathways related to synaptic regulation and immune cell activation.
Conclusions:
- Inpp5d haplodeficiency enhances microglial functions, leading to increased amyloid plaque clearance and cognitive preservation in the 5xFAD mouse model.
- Inhibition of INPP5D represents a promising therapeutic strategy for managing Alzheimer's disease pathology.
