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Single-molecule imaging reveals a?42:a?40 ratio-dependent oligomer growth on neuronal processes.

ABSTRACT: Soluble oligomers of the amyloid-? peptide have been implicated as proximal neurotoxins in Alzheimer's disease. However, the identity of the neurotoxic aggregate(s) and the mechanisms by which these species induce neuronal dysfunction remain uncertain. Physiologically relevant experimentation is hindered by the low endogenous concentrations of the peptide, the metastability of A? oligomers, and the wide range of observed interactions between A? and biological membranes. Single-molecule microscopy represents one avenue for overcoming these challenges. Using this technique, we find that A? binds to primary rat hippocampal neurons at physiological concentrations. Although amyloid-?(1-40) as well as amyloid-?(1-42) initially form larger oligomers on neurites than on glass slides, a 1:1 mix of the two peptides result in smaller neurite-bound oligomers than those detected on-slide or for either peptide alone. With 1 nM peptide in solution, A?40 oligomers do not grow over the course of 48 h, A?42 oligomers grow slightly, and oligomers of a 1:1 mix grow substantially. Evidently, small A? oligomers are capable of binding to neurons at physiological concentrations and grow at rates dependent on local A?42:A?40 ratios. These results are intriguing in light of the increased A?42:A?40 ratios shown to correlate with familial Alzheimer's disease mutations.

SUBMITTER: Johnson RD

PROVIDER: S-EPMC3576537 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Single-molecule imaging reveals aβ42:aβ40 ratio-dependent oligomer growth on neuronal processes.

Johnson Robin D RD Schauerte Joseph A JA Chang Chun-Chieh CC Wisser Kathleen C KC Althaus John Christian JC Carruthers Cynthia J L CJ Sutton Michael A MA Steel Duncan G DG Gafni Ari A

Biophysical journal 20130201 4

Soluble oligomers of the amyloid-β peptide have been implicated as proximal neurotoxins in Alzheimer's disease. However, the identity of the neurotoxic aggregate(s) and the mechanisms by which these species induce neuronal dysfunction remain uncertain. Physiologically relevant experimentation is hindered by the low endogenous concentrations of the peptide, the metastability of Aβ oligomers, and the wide range of observed interactions between Aβ and biological membranes. Single-molecule microscop ...[more]

PMID: 23442968

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Project description: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.

Dataset Information

Single-molecule imaging reveals a?42:a?40 ratio-dependent oligomer growth on neuronal processes.

Publications

Single-molecule imaging reveals aβ42:aβ40 ratio-dependent oligomer growth on neuronal processes.

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