Saturday, April 26, 2025
4/26/2025
Investigating pathways of hippocampal synaptic funtion: potential implications for Alzheimer's disease - Project Summary Alzheimer's Disease (AD) is a neurodegenerative disease affecting millions of people around the globe. AD pathology includes neuronal cell death, synaptic dysfunction, and corresponding behavioral deficits. However, the molecular basis underlying AD pathologies remains unclear. Glycerophosphodiester phosphodiesterase 2 (GDE2) is a member of a six-transmembrane protein family that releases glycosylphosphatidylinositol (GPI)-anchored proteins from the cell surface. In the developing nervous system, GDE2 promotes neuronal differentiation in the central nervous system (CNS) using its GPI-anchor cleavage mechanism. During aging the loss of GDE2 leads to AD-like phenotypes, including Aβ production, synaptic protein loss, and neurodegeneration. In human AD brain tissue, GDE2 aberrantly accumulates intracellularly compared to healthy control brains, suggesting that GDE2 dysfunction could contribute to AD pathophysiology. GDE2 mediates its functions in regulating Aβ production and synaptic protein loss via regulation of surface expression of the GPI-anchored protein RECK (reversion-inducing cysteine-rich protein with Kazal motifs). RECK is a potent inhibitor of metalloproteases and is recently implicated in canonical Wnt signaling. Increased expression of membrane RECK leads to a decrease in synaptic proteins that is independent of Aβ production and levels of membrane RECK are highly elevated in AD patient brain. The guiding hypothesis of this proposal is that GDE2 regulates synaptic function through the cleavage of RECK and that dysfunction of this pathway contributes to AD synaptic pathology and cognitive changes. I will test this hypothesis through a multi-pronged approach that will utilize electrophysiological, behavioral, and molecular approaches. In Aim 1, I will assess the requirement for GDE2 in pre- and post-synaptic function in mice. In Aim 2, I will perform a variety of behavioral experiments testing cognition to define corresponding behavioral abnormalities in mice lacking GDE2. Finally, in Aim 3, I will probe the molecular mechanism through which GDE2 and RECK act to affect synaptic biology. These experiments will expand our knowledge of the role GDE2 plays in synaptic biology and could potentially help us better understand the mechanistic basis of AD pathologies. This research will be performed in a highly collaborative environment, where I will have numerous opportunities to receive quality mentorship and training, to develop my written and presentation skills, and to grow as a mentor and teacher to more junior scientists. Overall, the Kirschstein-NRSA grant will support both my research aimed at discovering the synaptic biology underlying neurodegeneration and my development as an independent scientist.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).