title: Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A.
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.
authors: Department of Physiology, Pharmacology and Neuroscience, City University of New York Medical School, New York, New York 10031, USA. hywang@sci.ccny.cuny.edu
authors: Hoau-Yan
authors: HY
authors: Wang
authors: Kalindi
authors: K
authors: Bakshi
authors: Maya
authors: M
authors: Frankfurt
authors: Andres
authors: A
authors: Stucky
authors: Marissa
authors: M
authors: Goberdhan
authors: Sanket M
authors: SM
authors: Shah
authors: Lindsay H
authors: LH
authors: Burns
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003285:Contractile Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D064448:Filamins; D006801:Humans; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D003285:Contractile Proteins; D016207:Cytokines; D064448:Filamins; D008840:Microfilament Proteins; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D051197:Toll-Like Receptor 4; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); D016875:tau Proteins