PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis

• Published in: Neurobiology of aging Vol. 55; pp. 99 - 114
• Main Authors: Wang, Hoau-Yan, Lee, Kuo-Chieh, Pei, Zhe, Khan, Amber, Bakshi, Kalindi, Burns, Lindsay H
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2017
• Subjects: alpha7 Nicotinic Acetylcholine Receptor - metabolism; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - psychology; Alzheimer Disease - therapy; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - toxicity; Amyloid-beta; Animals; Cytokines - metabolism; Disease Models, Animal; Female; Filamins - chemistry; Filamins - metabolism; Inflammation Mediators - metabolism; Internal Medicine; Male; Mice, Transgenic; Molecular Targeted Therapy; Neurology; Neuronal Plasticity; Neuroprotective Agents - metabolism; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Peptide Fragments - metabolism; Peptide Fragments - toxicity; Phosphorylation - drug effects; Protein Binding; Receptor function; Scaffolding protein; Signal transduction; Tau phosphorylation; tau Proteins; Therapeutics; Toll-Like Receptor 4 - metabolism; Tau phosphorylation; Signal transduction; Receptor function; Scaffolding protein; Therapeutics; Amyloid-beta
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2017.03.016

Abstract We show that amyloid-β1-42 (Aβ42 ) triggers a conformational change in the scaffolding protein filamin A (FLNA) to induce FLNA associations with α7-nicotinic acetylcholine receptor (α7nAChR) and toll-like receptor 4 (TLR4). These aberrant associations respectively enable Aβ42 's toxic signaling via α7nAChR to hyperphosphorylate tau protein, and TLR4 activation to release inflammatory cytokines. PTI-125 is a small molecule that preferentially binds altered FLNA and restores its native conformation, restoring receptor and synaptic activities and reducing its α7nAChR/TLR4 associations and downstream pathologies. Two-month oral PTI-125 administration to triple-transgenic (3xTg) Alzheimer's disease (AD) mice before or after apparent neuropathology and to 8-month wildtypes with milder neuropathologies reduced receptor dysfunctions and improved synaptic plasticity, with some improvements in nesting behavior and spatial and working memory in 3xTg AD mice. PTI-125 also reduced tau hyperphosphorylation, aggregated Aβ42 deposition, neurofibrillary tangles, and neuroinflammation. Efficacy in postmortem AD and Aβ42 -treated age-matched control hippocampal slices was concentration-dependent starting at 1 picomolar (pM) concentration. PTI-125 is the first therapeutic candidate to preferentially bind an altered protein conformation and reverse this proteopathy.