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

Publication date: Available online 31 March 2017
Source:Neurobiology of Aging
Author(s): Hoau-Yan Wang, Kuo-Chieh Lee, Zhe Pei, Amber Khan, Kalindi Bakshi, Lindsay H. Burns
We show that A42 triggers a conformational change in the scaffolding protein filamin A (FLNA) to induce FLNA associations with 7-nicotinic acetylcholine receptor (7nAChR) and toll-like receptor 4 (TLR4). These aberrant associations respectively enable A42's toxic signaling via 7nAChR 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 7nAChR/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 A42 deposition, neurofibrillary tangles (NFTs) and neuroinflammation. Efficacy in postmortem AD and A42-treated age-matched control hippocampal slices was concentration-dependent starting at 1 pM. PTI-125 is the first therapeutic candidate to preferentially bind an altered protein conformation and reverse this proteopathy.



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