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. Epub 2017 Mar 31.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / psychology
  • Alzheimer Disease / therapy*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Cytokines / metabolism
  • Disease Models, Animal
  • Female
  • Filamins / chemistry*
  • Filamins / metabolism*
  • Inflammation Mediators / metabolism
  • Male
  • Mice, Transgenic
  • Molecular Targeted Therapy
  • Neuronal Plasticity
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Peptide Fragments / metabolism
  • Peptide Fragments / toxicity
  • Phosphorylation / drug effects
  • Protein Binding
  • Toll-Like Receptor 4 / metabolism
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism
  • tau Proteins


  • Amyloid beta-Peptides
  • Cytokines
  • FLNA protein, human
  • Filamins
  • Inflammation Mediators
  • Neuroprotective Agents
  • Peptide Fragments
  • Toll-Like Receptor 4
  • alpha7 Nicotinic Acetylcholine Receptor
  • amyloid beta-protein (1-42)
  • tau Proteins