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Dive into the research topics where Nicholas J. Izzo is active.

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Featured researches published by Nicholas J. Izzo.


PLOS ONE | 2014

Alzheimer's Therapeutics Targeting Amyloid Beta 1-42 Oligomers II: Sigma-2/PGRMC1 Receptors Mediate Abeta 42 Oligomer Binding and Synaptotoxicity

Nicholas J. Izzo; Jinbin Xu; Chenbo Zeng; Molly J. Kirk; Kelsie Mozzoni; Colleen Silky; Courtney Rehak; Raymond Yurko; Gary Charles Look; Gilbert Rishton; Hank Safferstein; Carlos Cruchaga; Alison Goate; Michael A. Cahill; Ottavio Arancio; Robert H. Mach; Rolf J. Craven; Elizabeth Head; Harry LeVine; Tara L. Spires-Jones; Susan M. Catalano

Amyloid beta (Abeta) 1–42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimers disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimers disease patients brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.


PLOS ONE | 2014

Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors Is Displaced by Drug Candidates That Improve Cognitive Deficits

Nicholas J. Izzo; Agnes Staniszewski; Lillian K. To; Mauro Fa; Andrew F. Teich; Faisal Saeed; Harrison Wostein; Thomas Walko; Anisha Vaswani; Meghan Wardius; Zanobia Syed; Jessica Ravenscroft; Kelsie Mozzoni; Colleen Silky; Courtney Rehak; Raymond Yurko; Patricia W. Finn; Gary Charles Look; Gilbert Rishton; Hank Safferstein; Miles C. Miller; Conrad E. Johanson; Edward G. Stopa; Manfred Windisch; Birgit Hutter-Paier; Mehrdad Shamloo; Ottavio Arancio; Harry LeVine; Susan M. Catalano

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1–42 oligomers is proposed to underlie cognitive decline in Alzheimers disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimers disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors - i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimers therapeutics.


Archive | 2012

Compositions and methods for treating neurodegenerative disease

Susan Catalano; Gilbert Rishton; Nicholas J. Izzo


Archive | 2017

composições e métodos para o tratamento de doenças neurodegenerativas

Gilbert Rishton; Nicholas J. Izzo; Susan Catalano


Archive | 2017

composições e métodos para tratar doença neurodegenerativa

Gilbert Rishton; Nicholas J. Izzo; Susan Catalano


Alzheimers & Dementia | 2017

A PHASE 1 SAFETY TRIAL OF THE Aβ OLIGOMER RECEPTOR ANTAGONIST CT1812

Susan Catalano; Michael Grundman; Lon S. Schneider; Steven T. DeKosky; Roger Morgan; Robert Guttendorf; Michelle Higgin; Julie Pribyl; Kelsie Mozzoni; Nicholas J. Izzo; Hank Safferstein


Alzheimers & Dementia | 2016

A TWO-PART, DOUBLE-BLIND, PLACEBO-CONTROLLED, PHASE 1 STUDY OF THE SAFETY AND PHARMACOKINETICS OF SINGLE AND MULTIPLE ASCENDING DOSES OF CT1812 IN HEALTHY VOLUNTEERS

Susan Catalano; Michael Grundman; Lon S. Schneider; Steven T. DeKosky; Roger Morgan; Michelle Higgin; Julie Pribyl; Kelsie Mozzoni; Nicholas J. Izzo; Hank Safferstein; Jason Lickliter


Neurology | 2014

An Abeta Oligomer Receptor Antagonist and Antibodies to Specific Target Receptor Epitopes Displace Abeta Oligomers in Alzheimer’s Patient Brain Tissue Sections (I11-1.001)

Susan Catalano; Nicholas J. Izzo; Courtney Rehak; Raymond Yurko; Kelsie Mozzoni; Colleen Silky; Gary Charles Look; Gilbert Rishton; Hank Safferstein; Tara L. Spires-Jones


Archive | 2012

Compositions et méthodes pour le traitement de maladies neurodégénératives

Susan Catalano; Gilbert Rishton; Nicholas J. Izzo


Archive | 2012

Zusammensetzungen und verfahren zur behandlung neurodegenerativer erkrankungen

Susan Catalano; Gilbert Rishton; Nicholas J. Izzo

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Lon S. Schneider

University of Southern California

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Alison Goate

Icahn School of Medicine at Mount Sinai

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