IUSM Alzheimer's Disease Drug Discovery Center

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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 and neuroinflammation in the etiology of AD. Microglia are the resident immune cells in brain that maintain 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. Genetic evidence suggests that lower expression of the cell surface microglial immune receptor known as Triggering receptor expressed on myeloid cells-2 (TREM2) and inactivating variants (e.g. R47H) of this receptor are correlated with an increased risk of developing of AD. Conversely, enhanced signaling downstream from TREM2 via the Phospholipase C gamma 2 (PLCγ2) P522R variant is protective. This genetic evidence suggests that dampened microglial activity increases risk of neurodegeneration while activated microglia are protective. Src homology 2 domain containing inositol polyphosphate 5-phosphatase 1 (SHIP1) is a member of the inositol polyphosphate-5-phosphatase (INPP5D) family, which has also been identified as a risk gene for AD. INPP5D encodes SHIP1, which is a phosphatidylinositol phosphatase that plays a key role regulating pathways downstream from TREM2 by binding immunoreceptor tyrosine-based inhibition motifs (ITIMs), competing with kinases, and modulating phosphatidylinositol-dependent signaling. We hypothesize that knockdown of INPP5D/SHIP1 will increase signaling downstream from TREM2 thus increasing microglial protective functions, which will result in a reduced rate of disease progression and cognitive decline in AD patients. To test this hypothesis, we will design and synthesize oligonucleotides for the efficient siRNA knockdown of INPP5D (Aim 1). We will develop a screening assay for the selection of oligonucleotides with optimal knockdown efficiency (Aim 2). Importantly, these oligonucleotides will be modified for efficient tissue distribution and knockdown efficiency in brain, which will allow the investigation of INPP5D silencing on microglial activity and related immunological responses in the 5xFAD murine model of AD (Aim 3). Our robust methodologies aim to elucidate the mechanistic impacts of SHIP1 on neuroinflammation, synaptic integrity, and broader neuropathological sequela associated with AD. Collectively, these studies will support the translation of a therapeutic siRNA into the clinic that will reduce neuroinflammation, amyloid burden, and improve cognition, thus advancing the NIH/NIA mission to develop novel therapies for AD.