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Inpp5d haplodeficiency alleviates tau pathology in the PS19 mouse model of Tauopathy
Disha M Soni1, Peter Bor-Chian Lin1, Audrey Lee-Gosselin1
1Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Introduction:
A noncoding variant (rs35349669) within INPP5D, a lipid and protein phosphatase restricted to microglia in the brain, is linked to increased susceptibility to Alzheimer's disease (AD). While Inpp5d is well-studied in amyloid pathology, its role in tau pathology remains unclear.
Methods:
PS19 Tauopathy mice were crossed with Inpp5d-haplodeficient (Inpp5d+/-) mice to examine the impact of Inpp5d in tau pathology.
Results:
Increased INPP5D expression correlated positively with phospho-Tau AT8 in PS19 mice. Inpp5d haplodeficiency mitigated hyperphosphorylated tau levels (AT8, AT180, AT100, and PHF1) and motor deficits in PS19 mice. Transcriptomic analysis revealed an up-regulation of genes associated with immune response and cell migration.
Discussion:
Our findings define an association between INPP5D expression and tau pathology in PS19 mice. Alleviation in hyperphosphorylated tau, motor deficits, and transcriptomics changes in haplodeficient-Inpp5d PS19 mice indicate that modulation in INPP5D expression may provide therapeutic potential for mitigating tau pathology and improving motor deficits.
Highlights:
The impact of Inpp5d in the context of tau pathology was studied in the PS19 mouse model. INPP5D expression is associated with tau pathology. Reduced Inpp5d expression in PS19 mice improved motor functions and decreased total and phospho-Tau levels. Inpp5d haplodeficiency in PS19 mice modulates gene expression patterns linked to immune response and cell migration. These data suggest that inhibition of Inpp5d may be a therapeutic approach in tauopathies.
Insights
Reduced expression of INPP5D, an enzyme linked to Alzheimer's disease risk, improved motor function and decreased tau pathology in a mouse model. This suggests INPP5D inhibition may be a therapeutic strategy for tauopathies.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- A genetic variant in INPP5D is associated with increased Alzheimer's disease (AD) susceptibility.
- The role of Inpp5d in tau pathology, a key feature of AD and other neurodegenerative diseases, is not well understood.
- Inpp5d is a phosphatase enzyme primarily found in microglia within the brain.
Purpose of the Study:
- To investigate the impact of Inpp5d on tau pathology.
- To explore the therapeutic potential of modulating Inpp5d expression in tauopathies.
Main Methods:
- PS19 tauopathy mouse model was crossed with Inpp5d-haplodeficient mice.
- Levels of hyperphosphorylated tau were assessed using specific antibodies (AT8, AT180, AT100, PHF1).
- Motor function and gene expression patterns were analyzed.
Main Results:
- Increased INPP5D expression correlated with elevated phospho-Tau levels in PS19 mice.
- Inpp5d haplodeficiency reduced hyperphosphorylated tau and improved motor deficits in PS19 mice.
- Transcriptomic analysis showed altered immune response and cell migration gene expression in Inpp5d-haplodeficient mice.
Conclusions:
- INPP5D expression is directly associated with tau pathology progression.
- Reducing Inpp5d levels ameliorates tau pathology and motor impairments in a mouse model.
- Inhibition of Inpp5d presents a potential therapeutic avenue for treating tauopathies.
