1. Amyloid Beta Peptides Block New Synapse Assembly by Nogo Receptor Mediated Inhibition of T-Type Calcium Channels
- Author
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Alexander K. Reed, Zachary P. Wills, Sivaprakash Sivaji, Alice Cheng, Michael C. Chiang, Haadi Ali, Sareen Ali, Alex Sklyar, Patrick Beukema, Jennifer Borowski, Zihan Guo, Yanjun Zhao, Georgia R. Frost, Ravindra Kodali, Bryan Kennedy, and Monica Zukowski
- Subjects
0301 basic medicine ,Male ,Nogo Receptors ,Amyloid beta ,chemistry.chemical_element ,Mice, Transgenic ,CHO Cells ,Calcium ,Inhibitory postsynaptic potential ,Article ,03 medical and health sciences ,Calcium Channels, T-Type ,Mice ,0302 clinical medicine ,Cricetulus ,Organ Culture Techniques ,Cricetinae ,Animals ,Humans ,Rats, Long-Evans ,Calcium Signaling ,Receptor ,Cells, Cultured ,Calcium signaling ,Mice, Knockout ,Amyloid beta-Peptides ,biology ,Voltage-dependent calcium channel ,Synapse assembly ,General Neuroscience ,T-type calcium channel ,Calcium Channel Blockers ,Peptide Fragments ,Rats ,030104 developmental biology ,HEK293 Cells ,chemistry ,Synapses ,biology.protein ,Female ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Summary 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
- Published
- 2017