Abstract
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.
Highlights
Disruption of the associative/dissociative balance in synaptic plasticity that is the basis of learning and memory begins in Mild Cognitive Impairment (MCI) and progresses as Alzheimer’s disease continues
While several cell surface proteins have been identified as receptors of accumulation of synaptotoxic beta amyloid (Abeta) oligomers [32], therapeutic ligands for these receptors have not been demonstrated to be effective in displacing bound Abeta oligomers
Neuronal cell lines can be used in high-throughput screens, but they do not replicate the electrophysiological state-dependent signaling of primary neuronal cultures and are unlikely to adequately model the subtle alterations in this signaling that are caused by oligomers during the earliest manifestations of the disease state [44]
Summary
Disruption of the associative/dissociative balance in synaptic plasticity that is the basis of learning and memory begins in Mild Cognitive Impairment (MCI) and progresses as Alzheimer’s disease continues. Evidence suggests this cognitive decline is caused by the accumulation of Abeta 1–42 oligomers in the brains of these patients [1,2,3,4,5,6] Oligomers disrupt this balance by binding to plasma membrane proteins [7,8,9,10,11,12,13,14,15], changing intracellular calcium levels [11,16,17,18], inducing tau mislocalization, disrupting microtubules [17,18], altering membrane trafficking processes and surface expression levels of critical synaptic ion channels [19,20,21] and causing reversible spine loss in neurons [17,22,23,24,25]. There is disagreement over the identity of the form of Abeta oligomer responsible for human cognitive loss, creating difficulty in extrapolating in vitro results to in vivo efficacy
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