# Alzheimer's Disease: simultaneous modulation of NMDAR, BACE1, APP and Fyn activity by palmitoylation-targeting CIRC825 > **NIH NIH R43** · CIRCUMVENT PHARMACEUTICALS, INC. · 2021 · $507,284 ## Abstract PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) has predominantly been characterized by amyloid plaques and neurofibrillary tau tangles, and soluble oligomers of these peptides are thought to be toxic; hence, targeting these histopathological hallmarks has led to a long series of clinical trials, but to date they have all failed. Intriguingly, aberrant palmitoylation of multiple proteins has been reported in AD. Accordingly, we seek here to simultaneously modulate the location and activity of multiple AD-associated proteins (neurotransmitter receptor NMDAR, amyloid plaque-associated BACE1 and APP, and neurofibrillary tangle-associated Fyn kinase) by altering their shared post-translational modification, palmitoylation. To this effort, we will transfer learnings from a drug development program of a small molecule that removes palmitate from proteins, N-(tert-butyl)-hydroxylamine (NtBuHA, called CIRC825) in the well-defined neurodegenerative disease that is associated with over- palmitoylation, CLN1 Batten (CLN1). Of great importance to this AD-related grant, extrasynaptic (e)NMDARs containing predominantly GluN2B subunits have been implicated to be overactivated in the pathogenesis of AD. In a feasibility study demonstrating our approach will work in the context of human AD, our preliminary findings have recently shown that CIRC825 treatment virtually eliminates the aberrant hyperexcitable phenotype in human AD hiPSC cerebrocortical neurons compared to WT. Additionally as feasibility data, we investigated CIRC825 in CHOAPP cells (which overexpress APP), and found it lowered palmitoylation of APP, and it decreased Aβ42 generation (the pathogenic form) without decreasing soluble Aβ40. The aims of this Phase 1 work are focused on expanding our understanding the pathomolecular importance of the palmitoylation of APP, BACE1, Fyn, and NMDAR in both Cln1-/- mouse neurons and in human (h)iPSC-derived 2D cortical neuronal cultures and 3D cerebral organoids that have familial AD mutations. Human iPSCs to be used include wPSEN1 M146V/WT and APPswe/WT hiPSC lines as well as the PSEN1 ΔE9/WT hiPSC line (with WT isogenic controls). We will modulate palmitoylation in these models by treating them with CIRC825. Finally, in a Cln1-/- mouse model, we will compare physiologic benefits of CIRC825 to those of memantine. Specifically, in aim 1 we will evaluate CIRC825 in cultured CLN1-/- neurons and (h)iPSC-derived AD neurons for 1) effects on decreasing palmitoylation of APP, BACE1, Fyn, and NMDAR; 2) suppression of extra-synaptic dendritic Ca2+ influxes by calcium imaging, and 3) mitigation of glutamate-induced cell death in an excitotoxicity assay. In aim 2 we will test concentration-dependent physiologic effects of CIRC825 on (h)iPSC-derived 3D cerebral organoids (with familial AD mutations and WT controls), using multiple assays including patch-clamp electrophysiology, calcium imaging, multi-electrode array experiments, and immunohistochemistry. In aim 3 we will... ## Key facts - **NIH application ID:** 10257994 - **Project number:** 1R43AG072984-01 - **Recipient organization:** CIRCUMVENT PHARMACEUTICALS, INC. - **Principal Investigator:** Devin Thomas Wiley - **Activity code:** R43 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2021 - **Award amount:** $507,284 - **Award type:** 1 - **Project period:** 2021-07-15 → 2023-12-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10257994 ## Citation > US National Institutes of Health, RePORTER application 10257994, Alzheimer's Disease: simultaneous modulation of NMDAR, BACE1, APP and Fyn activity by palmitoylation-targeting CIRC825 (1R43AG072984-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10257994. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*