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Regulation of NPTX Shedding - Implications for Synaptic Organizations and Function

Award Number: F31AG099539
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/06/2027
PERIOD OF PERFORMANCE END DATE: 02/05/2028

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Regulation of NPTX Shedding - Implications for Synaptic Organizations and Function - Project Summary: The underlying mechanisms of cognitive decline in Alzheimer’s Disease (AD) are poorly understood. Bridging this knowledge gap is critical to understanding the basis of cognitive deficits in AD and finding therapeutic solutions to mitigate the consequences of this devastating disease. The neural pentraxins (NPTXs) are important players in synaptic biology. They form a complex that acts in trans to stabilize synaptic connections, and their release is essential for homeostatic scaling, which is important for information processing. NPTX complex release is mediated by metalloprotease-dependent cleavage; however, the regulatory pathways that control NPTX release have not yet been fully elucidated. Deciphering this control mechanism is crucial because NPTX release is robustly reduced in AD and is thought to contribute to cognitive defects in disease. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is an important regulator of metalloprotease function in the developing and adult nervous system. GDE2 is the only known protein in vertebrates that acts at the cell surface in neurons to cleave the glycosylphosphatidylinositol (GPI) anchor that tethers a subclass of proteins to the membrane. It activates metalloproteases such as ADAM10 (A Disintegrin and metalloproteinase domain-containing protein 10) via its cleavage and inactivation of the GPI-anchored metalloprotease inhibitor RECK (Reversion inducing cysteine-rich protein with Kazal motifs). We previously showed that GDE2 cleavage of RECK stimulates ADAM10 α-secretase cleavage of Amyloid Precursor Protein (APP) to prevent amyloid production. Notably, GDE2 shows aberrant intracellular accumulation in neurons in patients with AD, and biochemical studies of postmortem AD brain confirm increased membrane RECK and decreased soluble RECK in line with GDE2 dysfunction. Thus, disruption of the GDE2/RECK regulatory axis is hypothesized to contribute to amyloid pathologies in AD via metalloprotease inhibition. Whether the GDE2/RECK axis regulates metalloprotease-dependent shedding of NPTXs is unclear. Preliminary studies of cultured Gde2KO neurons, known to have elevated RECK surface expression, show reduced release of NPTXs. Further, studies in HEK293 cells show that RECK expression is sufficient to inhibit the release of the NPTX complex. These observations suggest the hypothesis that GDE2 regulation of RECK regulates the metalloprotease-dependent release of NTPXs, and the failure of this pathway leads to synaptic abnormalities. In Aim 1, I will utilize heterologous cells to define the basis of RECK inhibition of NPTX release and determine the mechanism of GDE2 inactivation of RECK. In Aim 2, I will utilize primary neurons to determine if GDE2 regulation of RECK surface expression regulates endogenous NPTX shedding and to examine the consequences of GDE2 loss on NPTX localization and shedding. In Aim 3, I will determine how the loss of GDE2 affects NPTX2 localization at the synapse and general synaptic integrity. Together, the outcomes of my project will clarify the mechanisms of NPTX release from neurons, which may provide insight into underlying mechanisms of cognitive decline in AD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $34,114 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Aging Research	000	1	8/6/2026	NEW	$34,114
														Subtotal = $34,114

Grand Total All Awards = $34,114

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Regulation of NPTX Shedding - Implications for Synaptic Organizations and Function

Award Number: F31AG099539

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/06/2027

PERIOD OF PERFORMANCE END DATE: 02/05/2028

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