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

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

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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.

PMID:
22815492
DOI:
10.1523/JNEUROSCI.0354-12.2012
[Indexed for MEDLINE]
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