Wednesday, April 2, 2025
4/2/2025
Optimization of SHIP1 Inhibitors for the Treatment of Alzheimer's Disease - PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is a fatal neurodegenerative condition characterized by cognitive decline, β- amyloid (Aβ) plaques, and tau-containing neurofibrillary tangles (NFTs). Recent human genetic evidence supports an important role for microglia in the etiology of AD. Microglia are the resident immune cells in the brain and play important roles in maintaining neuronal health and proper immunomodulation of neighboring glial cells. Microglia clear neurotoxins, Aβ oligomers, and Aβ plaques, and thereby mitigate an inflammatory microenvironment that is toxic to neurons. Lower expression of TREM2, a cell surface microglial immune receptor, and hypomorphic variants (e.g. R47H), are correlated with an increased risk of developing of AD. Conversely, enhanced signaling downstream from TREM2 via the hypermorphic P522R variant of PLCγ2 reduces risk for AD. This human genetic evidence suggests that microglia that are more sensitive to TREM2- mediated signaling protect against neurodegeneration. Src homology 2 domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1) is a member of the inositol polyphosphate-5-phosphatase (INPP5) family of phosphatidylinositol phosphatases. INPP5D, the gene that encodes SHIP1, has also been identified as a risk gene for AD. SHIP1, plays a key role regulating pathways downstream from immune receptors, including TREM2 and FcγRIIB. SHIP1, binds immunoreceptor tyrosine-based inhibition motifs (ITIMs) where it competes with kinases and modulates phosphatidylinositol-dependent signaling. We hypothesize that inhibition of SHIP1 will improve TREM2-mediated microglial responses to neurotoxins, and promote an overall neuroprotective phenotype to microglial states , and thereby slow cognitive decline. Furthermore, since recently approved disease modifying anti-Aβ antibodies depend in part on Fc receptor activation of microglia, SHIP1 inhibitors may also be combined with anti-Aβ antibodies to improve their efficacy. To test this hypothesis, we will optimize the potency and drug-like properties of SHIP1 inhibitors from identified chemical scaffolds (Aim 1). We will identify the effect of SHIP1 inhibition on microglial states in mouse brain, define pharmacokinetic (PK) and pharmacodynamic (PD) relationships, and determine the level and duration of SHIP1 inhibition required for efficacy in a mouse model of AD (Aim 2). With an understanding of the target engagement required for efficacy, SHIP1 inhibitors with sufficient human potency and drug-like properties will be used to develop target engagement and translational biomarker assays for human studies (Aim 3). Collectively, these studies will support the translation of new molecular entities into the clinic that will reduce neuroinflammation and amyloid burden and improve cognition, thus advancing the NIH/NIA mission to develop novel therapies for AD.
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