# Determining the effect of INPP5D/SHIP1 deficiency in neuroinflammation and Alzheimer's disease pathologies

> **NIH NIH F32** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $75,919

## Abstract

PROJECT SUMMARY
 Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with aging and is the most
common cause of dementia. In recent years, genetic studies have revealed a number of risk loci in or near genes
expressed in microglia, suggesting a key role for microglia in AD pathogenesis. Inositol polyphosphate-5-
phosphatase D (INPP5D) is one of the microglia-specific targets converged on by these genetic studies. INPP5D
is primarily expressed by cells of the hematopoietic lineage, including microglia, and encodes a 5’ phosphatase
protein known as SHIP1. INPP5D/SHIP1 is a negative regulator of immune cell surface receptors, including
TREM2/TYROBP, by catalyzing the conversion of PI(3,4,5)P3 to PI(3,4)P2 to prevent receptor activation and
downstream signaling, counteracting the PI3K/mTOR pathway. SHIP1 limits microglia functions associated with
survival, proliferation and phagocytosis. INPP5D could be an important target for microglia-focused AD
therapies, although it is still unknown how decreasing or increasing INPP5D expression affects pathology or
behavioral outcomes in vivo. Inhibiting INPP5D expression promotes microglial proliferation, and phagocytosis,
each of which is considered to be an important potential cellular phenotype for preventing or reducing AD
pathology and improving disease outcomes.
 The aim of this proposal is to increase our understanding of the function of INPP5D/SHIP1 in the microglial
response in diseased brain. We will use Inpp5dflox mice crossed with an inducible CX3CR1-CreER, in which
tamoxifen-induced Cre expression results in persistent recombination in long-lived microglia, but not short-lived
myeloid cells. For each aim, we will induce microglia-specific knockdown in models representing the pathological
hallmarks of AD, Aβ deposition (APPKM670/671NL/PSEN1Δexon9) in Aim 1 and tauopathy (MAPTP301S) in Aim 2. We
hypothesize that Inpp5d/SHIP1 deficiency outcomes are driven by TYROBP overexpression/upregulation, i.e.
ameliorated pathogenic forms of amyloid pathology and cognitive deficits in amyloid mouse model but
exacerbated tau pathology and cognitive deficits in tauopathy model. Importantly, pharmacological targeting both
to activate and inhibit SHIP1 are being explored. It is necessary to understand the role of Inpp5d/SHIP1 in
diseased brain before further drug testing. It is our hope that with the understanding gained in this proposal, we
will be able to appropriately target Inpp5d/SHIP1 for disease and begin the next steps to test these compounds
for their efficacy in brain with the intent to translate to the clinic.

## Key facts

- **NIH application ID:** 10465718
- **Project number:** 1F32AG077900-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Emilie Castranio
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $75,919
- **Award type:** 1
- **Project period:** 2022-09-30 → 2024-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465718

## Citation

> US National Institutes of Health, RePORTER application 10465718, Determining the effect of INPP5D/SHIP1 deficiency in neuroinflammation and Alzheimer's disease pathologies (1F32AG077900-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10465718. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*