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Neuron. 2017 Oct 11;96(2):355-372.e6. doi: 10.1016/j.neuron.2017.09.041.

Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor-Mediated Inhibition of T-Type Calcium Channels.

Author information

1
Department of Neurobiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
2
Department of Neurobiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
3
Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
4
Center for the Neural Basis of Cognition, Carnegie Mellon University, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
5
Department of Neurobiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA. Electronic address: zpwills@pitt.edu.

Abstract

Compelling evidence links amyloid beta (Aβ) peptide accumulation in the brains of Alzheimer's disease (AD) patients with the emergence of learning and memory deficits, yet a clear understanding of the events that drive this synaptic pathology are lacking. We present evidence that neurons exposed to Aβ are unable to form new synapses, resulting in learning deficits in vivo. We demonstrate the Nogo receptor family (NgR1-3) acts as Aβ receptors mediating an inhibition of synapse assembly, plasticity, and learning. Live imaging studies reveal Aβ activates NgRs on the dendritic shaft of neurons, triggering an inhibition of calcium signaling. We define T-type calcium channels as a target of Aβ-NgR signaling, mediating Aβ's inhibitory effects on calcium, synapse assembly, plasticity, and learning. These studies highlight deficits in new synapse assembly as a potential initiator of cognitive pathology in AD, and pinpoint calcium dysregulation mediated by NgRs and T-type channels as key components. VIDEO ABSTRACT.

KEYWORDS:

FRET imaging; ICV injections; Nogo receptors; RCaMP sensor; RhoA2G sensor; T-type calcium channels; amyloid beta peptides; calcium dysfunction; new synapse assembly

PMID:
29024660
PMCID:
PMC6101033
DOI:
10.1016/j.neuron.2017.09.041
[Indexed for MEDLINE]
Free PMC Article

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