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

Abstract

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.

• Authors: Hoau-Yan Wang, Erika Cecon, Julie Dam, Zhe Pei, Ralf Jockers, Lindsay H Burns
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 18 (Sep 11 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37762230 (Publication Type: Journal Article)

Chemical References

• Amyloid beta-Peptides
• alpha7 Nicotinic Acetylcholine Receptor
• Filamins
• Simufilam
• Peptide Fragments

Topics

• Mice
• Humans
• Animals
• Alzheimer Disease (metabolism)
• Amyloid beta-Peptides (metabolism)
• alpha7 Nicotinic Acetylcholine Receptor (metabolism)
• Filamins (metabolism)
• Mice, Transgenic
• Peptide Fragments (metabolism)