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

Hoau-Yan Wang; Kalindi Bakshi; Maya Frankfurt; Andres Stucky; Marissa Goberdhan; Sanket M Shah; Lindsay H Burns

doi:10.1523/JNEUROSCI.0354-12.2012

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

J Neurosci. 2012 Jul 18;32(29):9773-84. doi: 10.1523/JNEUROSCI.0354-12.2012.

Authors

Hoau-Yan Wang¹, Kalindi Bakshi, Maya Frankfurt, Andres Stucky, Marissa Goberdhan, Sanket M Shah, Lindsay H Burns

Affiliation

¹ Department of Physiology, Pharmacology and Neuroscience, City University of New York Medical School, New York, New York 10031, USA. hywang@sci.ccny.cuny.edu

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism*
Alzheimer Disease / pathology
Amyloid beta-Peptides / metabolism*
Animals
Brain / drug effects*
Brain / metabolism
Brain / pathology
Contractile Proteins / antagonists & inhibitors*
Contractile Proteins / metabolism
Cytokines / metabolism
Female
Filamins
Humans
Male
Mice
Microfilament Proteins / antagonists & inhibitors*
Microfilament Proteins / metabolism
Neurofibrillary Tangles / drug effects
Neurofibrillary Tangles / metabolism
Neurofibrillary Tangles / pathology
Peptide Fragments / metabolism*
Phosphorylation / drug effects
Receptors, N-Methyl-D-Aspartate / metabolism
Receptors, Nicotinic / metabolism
Toll-Like Receptor 4 / metabolism
alpha7 Nicotinic Acetylcholine Receptor
tau Proteins / metabolism

Substances

Amyloid beta-Peptides
Chrna7 protein, human
Chrna7 protein, mouse
Contractile Proteins
Cytokines
Filamins
Microfilament Proteins
Peptide Fragments
Receptors, N-Methyl-D-Aspartate
Receptors, Nicotinic
Toll-Like Receptor 4
alpha7 Nicotinic Acetylcholine Receptor
amyloid beta-protein (1-42)
tau Proteins