Description
A Role for Nogo Receptor Mediated Inhibition of Synapse Assembly in Amyloid Peptide Dependent Learning Deficits in AD Mouse Models
Yanjun Zhao1, Sivaprakash Sivaji1, Michael C. Chiang1,4, Haadi Ali1, Monica Zukowski1, Sareen Ali1, Bryan Kennedy1, Alex Sklyar1, Ravindra Kodali2, Patrick Beukema3,4, Yang Bai5, Wen-Biao Gan5,6, Zachary P. Wills1,4*
1Department of Neurobiology, University of Pittsburgh, 2Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases, 3Center for the Neural Basis of Cognition, Carnegie Mellon University, 4Center for Neuroscience, University of Pittsburgh, 5Drug Discovery Center, Peking University Shenzhen Graduate School, 6 Department of Neuroscience and Physiology, New York University School of Medicine, *Corresponding Author
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 recently published work (Zhao et al., 2017) that neurons exposed to Aβ peptides are unable to form new synapses, resulting in learning deficits in vivo. We demonstrate the Nogo receptor family (NgR1-3) act as Aβ receptors mediating an inhibition of synapse assembly, plasticity and learning. Dual sensor imaging studies reveal Aβ activates NgRs on the dendrites of neurons triggering an inhibition of calcium signaling. We define T-type calcium channels as targets of Aβ-NgR signaling on dendrites, mediating Aβ's inhibitory effects on calcium, synapse assembly, plasticity and learning. Our imaging also identifies dendritic spines as sites where Aβ triggers an acute influx of calcium dependent on NMDARs. These imaging studies suggest Aβ binds distinct receptors in different cellular domains to compromise unique neuronal functions. Interestingly, we observe similar calcium signaling deficits in pyramidal neuron dendrites in vivo in (1) young fAD (familial) mice and (2) following local application of Aβ peptides in the cortex (Bai et al., 2017). In preliminary work, we identify specific learning deficits in these fAD mice that will allow us to address whether blocked new spine assembly drives memory loss in this AD mouse model, by two-photon imaging of spines in vivo. Our studies highlight deficits in new synapse assembly as a potential initiator of cognitive decline in AD, and pinpoint calcium dysregulation in dendrites mediated by NgRs and T-type channels as key components in this pathology.