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.

Disease-Modifying Treatments and Their Future in Alzheimer’s Disease Management

“…Simufilam is a small molecule DMT in this class that acts through the inhibition of Filamin-A, a scaffolding and regulator protein of the actin cytoskeleton [7]. In some experimental systems, Filamin-A was reported to be involved in the stabilization of the highaffinity interactional state of soluble amyloid-β-42 and the α-7 nicotinic acetylcholine receptor [15]. The interaction between amyloid-β-42 and the α-7 nicotinic acetylcholine receptor triggers tau protein phosphorylation and leads to synaptic dysfunction [15].…”

“…In some experimental systems, Filamin-A was reported to be involved in the stabilization of the highaffinity interactional state of soluble amyloid-β-42 and the α-7 nicotinic acetylcholine receptor [15]. The interaction between amyloid-β-42 and the α-7 nicotinic acetylcholine receptor triggers tau protein phosphorylation and leads to synaptic dysfunction [15]. Filamin-A suppression by simufilam can therefore indirectly decrease abnormal tau protein phosphorylation in hopes of improving synaptic functioning in those with AD [7].…”

Neurodegenerative Disease: From Molecular Basis to Therapy

“…Hoau-Yan Wang and colleagues [10] investigated the molecular mechanisms of simufilam, a novel oral drug candidate in phase 3 clinical trials for Alzheimer's dementia. Simufilam is a small molecule that binds an altered form of filamin A (FLNA) found in AD.…”