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.
Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's 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 Alzheimer's 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 Alzheimer's therapeutics.
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Nicholas J
NJ
Izzo
Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
Agnes
A
Staniszewski
Stanford University Medical School Behavioral and Functional Neuroscience Laboratory, Palo Alto, California, United States of America.
Lillian
L
To
Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
Mauro
M
Fa
Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
Andrew F
AF
Teich
Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
Faisal
F
Saeed
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Harrison
H
Wostein
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Thomas
T
Walko
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Anisha
A
Vaswani
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Meghan
M
Wardius
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Zanobia
Z
Syed
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Jessica
J
Ravenscroft
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Kelsie
K
Mozzoni
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Colleen
C
Silky
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Courtney
C
Rehak
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Raymond
R
Yurko
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Patricia
P
Finn
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Gary
G
Look
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Gilbert
G
Rishton
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Hank
H
Safferstein
Department of Pathology and Neurosurgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
Miles
M
Miller
Department of Pathology and Neurosurgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
Conrad
C
Johanson
Department of Pathology and Neurosurgery, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, United States of America.
Edward
E
Stopa
NeuroScios, GmbH, Graz, Austria.
Manfred
M
Windisch
QPS Austria GmbH, Grambach, Austria.
Birgit
B
Hutter-Paier
Stanford University Medical School Behavioral and Functional Neuroscience Laboratory, Palo Alto, California, United States of America.
Mehrdad
M
Shamloo
Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
Ottavio
O
Arancio
Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.
Harry
H
LeVine
Cognition Therapeutics Inc., Pittsburgh, Pennsylvania, United States of America.
Susan M
SM
Catalano
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001921:Brain / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)