2. Academic Validation
  3. PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis

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

  • Neurobiol Aging. 2017 Jul:55:99-114. doi: 10.1016/j.neurobiolaging.2017.03.016.
Hoau-Yan Wang 1,  Kuo-Chieh Lee 2,  Zhe Pei 2,  Amber Khan 3,  Kalindi Bakshi 2,  Lindsay H Burns 4
Affiliations

Affiliations

  • 1 Department of Physiology, Pharmacology and Neuroscience, City University of New York School of Medicine, New York, NY, USA; Department of Biology and Neuroscience, Graduate school of the City University of New York, New York, NY, USA. Electronic address: hywang@med.cuny.edu.
  • 2 Department of Physiology, Pharmacology and Neuroscience, City University of New York School of Medicine, New York, NY, USA.
  • 3 Department of Physiology, Pharmacology and Neuroscience, City University of New York School of Medicine, New York, NY, USA; Department of Biology and Neuroscience, Graduate school of the City University of New York, New York, NY, USA.
  • 4 Pain Therapeutics, Inc, Austin, TX, USA.
PMID: 28438486 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.

Keywords

Amyloid-beta; Receptor function; Scaffolding protein; Signal transduction; Tau phosphorylation; Therapeutics.

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