Reducing amyloid-related Alzheimer’s disease pathogenesis by a small molecule targeting filamin A

Bibliographic

Year of Publication: 
2012
Contact PI Name: 
Hoau-Yan Wang
Contact PI Affiliation: 
Department of Physiology, Pharmacology and Neuroscience, City University of New York Medical School, New York, New York, USA
Co-Authors: 
Kalindi Bakshi, Maya Frankfurt, Andres Stucky, Marissa Goberdhan, Sanket M. Shah, Lindsay H. Burns
Primary Reference (PubMED ID): 
Funding Source:
Study Goal and Principal Findings: 

PTI-125 is a novel compound demonstrating a promising new approach to treating Alzheimer's disease (AD), characterized by neurodegeneration and amyloid plaque and neurofibrillary pathologies. We show that the toxic signaling of amyloid-β(42) (Aβ(42)) by the α7-nicotinic acetylcholine receptor (α7nAChR), which results in tau phosphorylation and formation of neurofibrillary tangles, requires the recruitment of the scaffolding protein filamin A (FLNA). By binding FLNA with high affinity, PTI-125 prevents Aβ(42)'s toxic cascade, decreasing phospho-tau and Aβ aggregates and reducing the dysfunction of α7nAChRs, NMDARs, and insulin receptors. PTI-125 prevents Aβ(42) signaling by drastically reducing its affinity for α7nAChRs and can even dissociate existing Aβ(42)-α7nAChR complexes. Additionally, PTI-125 prevents Aβ-induced inflammatory cytokine release by blocking FLNA recruitment to toll-like receptor 4, illustrating an anti-inflammatory effect. PTI-125's broad spectrum of beneficial effects is demonstrated here in an intracerebroventricular Aβ(42) infusion mouse model of AD and in human postmortem AD brain tissue.

Therapeutic Agent

Therapeutic Information: 
Therapy Type:

Animal Model

Model Information: 
Species:
Model Type:
Strain/Genetic Background: 
E129

Experimental Design

Is the following information reported in the study?: 
Power/Sample Size Calculation
Blinded for Treatment
Pharmacokinetic Measures
Toxicology Measures
Biomarkers
Formulation
Duration of Treatment
Age of Animal at the Beginning of Treatment
Sex as a Biological Variable
Number of Premature Deaths
Statistical Plan
Inclusion/Exclusion Criteria Included
Randomized into Groups
Blinded for Outcome Measures
Pharmacodynamic Measures
ADME Measures
Dose
Route of Delivery
Frequency of Administration
Age of Animal at the End of Treatment
Study Balanced for Sex as a Biological Variable
Number of Excluded Animals
Genetic Background
Conflict of Interest

Outcomes

Outcomes: 
Outcome MeasuredOutcome Parameters
Biochemical
  • Calcium Influx
  • Filamin A
  • Interleukin 1 beta (IL-1 beta)
  • Interleukin 6 (IL-6)
  • Insulin Receptor beta
  • Insulin Receptor Substrate 1 (IRS1)
  • Neuronal Nitric Oxide Synthase (nNOS)
  • Nicotinic Acetylcholine Receptor alpha 7
  • Nicotinic Acetylcholine Receptor alpha 7 Activation
  • Glutamate Ionotropic Receptor NMDA Type Subunit 1 (GRIN1/NR1)
  • Phospholipase C gamma 1
  • phospho-Tau
  • phospho-Tau/Total Tau Protein
  • Protein Kinase C gamma (PKC gamma)
  • Postsynaptic Density Protein 95 (PSD95)
  • NMDAR/phospho-NMDAR
  • Tumor Necrosis Factor alpha (TNF alpha)
  • Toll-like Receptor 4 (TLR4)
  • EC50
  • NMDA Receptor Activity
  • Immunochemistry
  • Brain-beta Amyloid Peptide 42
  • PHF Tau
  • phospho-Tau