Simufilam Reverses Aberrant Receptor Interactions of Filamin A in Alzheimer's Disease

by Selleckchem | Dec 16 2023

Simufilam is a novel oral drug candidate in Phase 3 clinical trials for Alzheimer's disease (AD) dementia. This small molecule binds an altered form of filamin A (FLNA) that occurs in AD. This drug action disrupts FLNA's aberrant linkage to the α7 nicotinic acetylcholine receptor (α7nAChR), thereby blocking soluble amyloid beta1-42 (Aβ42)'s signaling via α7nAChR that hyperphosphorylates tau. Here, we aimed to clarify simufilam's mechanism. We now show that simufilam reduced Aβ42 binding to α7nAChR with a 10-picomolar IC50 using time-resolved fluorescence resonance energy transfer (TR-FRET), a robust technology to detect highly sensitive molecular interactions. We also show that FLNA links to multiple inflammatory receptors in addition to Toll-like receptor 4 (TLR4) in postmortem human AD brains and in AD transgenic mice: TLR2, C-X-C chemokine receptor type 4 (CXCR4), C-C chemokine receptor type 5 (CCR5), and T-cell co-receptor cluster of differentiation 4 (CD4). These aberrant FLNA linkages, which can be induced in a healthy control brain by Aβ42 incubation, were disrupted by simufilam. Simufilam reduced inflammatory cytokine release from Aβ42-stimulated human astrocytes. In the AD transgenic mice, CCR5-G protein coupling was elevated, indicating persistent activation. Oral simufilam reduced both the FLNA-CCR5 linkage and the CCR5-G protein coupling in these mice, while restoring CCR5's responsivity to C-C chemokine ligand 3 (CCL3). By disrupting aberrant FLNA-receptor interactions critical to AD pathogenic pathways, simufilam may promote brain health.

Comments:

Thank you for providing detailed information about simufilam and its mechanism of action in Alzheimer's disease (AD). Based on the information you provided, it seems that simufilam acts by binding to an altered form of filamin A (FLNA) that occurs in AD. This binding disrupts FLNA's aberrant linkage to the α7 nicotinic acetylcholine receptor (α7nAChR), preventing soluble amyloid beta1-42 (Aβ42) from signaling via α7nAChR and hyperphosphorylating tau. The disruption of this signaling pathway is crucial in preventing the progression of AD.

Additionally, you mentioned that simufilam reduces Aβ42 binding to α7nAChR with a 10-picomolar IC50 using time-resolved fluorescence resonance energy transfer (TR-FRET), demonstrating its high sensitivity in detecting molecular interactions. Furthermore, simufilam disrupts aberrant FLNA linkages to multiple inflammatory receptors, such as Toll-like receptor 2 (TLR2), C-X-C chemokine receptor type 4 (CXCR4), C-C chemokine receptor type 5 (CCR5), and T-cell co-receptor cluster of differentiation 4 (CD4), in postmortem human AD brains and AD transgenic mice. These abnormal FLNA-receptor interactions play a significant role in AD pathogenic pathways.

Simufilam's ability to disrupt these aberrant FLNA-receptor interactions not only prevents tau hyperphosphorylation but also reduces inflammatory cytokine release from Aβ42-stimulated human astrocytes. In AD transgenic mice, simufilam reduces the FLNA-CCR5 linkage and CCR5-G protein coupling, indicating a decrease in persistent activation. Simufilam also restores CCR5's responsivity to C-C chemokine ligand 3 (CCL3). By targeting these critical pathways, simufilam may promote brain health and potentially offer a promising treatment approach for Alzheimer's disease.

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