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

Hoau-Yan Wang; Kuo-Chieh Lee; Zhe Pei; Amber Khan; Kalindi Bakshi; Lindsay H Burns

doi:10.1016/j.neurobiolaging.2017.03.016

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.

Authors

Hoau-Yan Wang¹, Kuo-Chieh Lee², Zhe Pei², Amber Khan³, Kalindi Bakshi², Lindsay H Burns⁴

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-β_1-42 (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

Substances

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