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Neuroscience

Name
Ilya
Surname
Bezprozvanny
Scientific organization
Peter the Great St Petersburg Polytechnical University
Academic degree
D.Sci, PhD
Position
Professor
Scientific discipline
Life Sciences & Medicine
Topic
Neuroscience
Abstract
Store-operated calcium channel complex in postsynaptic spines: a new therapeutic target for Alzheimer’s disease treatment.

Elena Popugaeva1, Ekaterina Pchitskaya1, Hua Zhang2, Suya Sun2, and Ilya Bezprozvanny1,2

1Laboratory of Molecular Neurodegeneration (LMN), St Petersburg State Polytechnical University, St Petersburg, 19525, Russia
2Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Keywords
Alzheimer's disease, synapse, calcium signaling, imaging, neurodegeneration
Summary

Mushroom dendritic spine structures are essential for memory storage.  In the previous studies we suggested that the loss of mushroom spines may explain memory defects in aging and Alzheimer’s disease (AD).  We further demonstrated that the stability of mushroom spines depends on STIM2-mediated neuronal store operated calcium (Ca2+) influx (nSOC) pathway which is compromised in AD mouse models, in aging neurons and in sporadic AD patients (Sun at al,  2014, Neuron,  vol 82, pp 79-93;  Zhang at al,  J. Neuroscience, vol 35, pp 13275-13286;  Popugaeva at al, 2015, Molecular Neurodegeneration, 10:37).    The molecular identity of channel encoding SOC influx in spines remains unknown.   We now demonstrate that TRPC6 and Orai2 channels form a STIM2-regulated nSOC Ca2+ channel complex in hippocampal mushroom spines.   We further demonstrate that a known TRPC6 activator hyperforin and a novel nSOC positive modulator NSN21778 can stimulate activity of nSOC pathway in the spines and rescue mushroom spine loss in both presenilin and APP knock-in mouse models of AD. We further show that NSN21778 rescues hippocampal long-term potentiation impairment in APP knock-in mouse model.  We conclude that STIM2-regulated TRPC6/Orai2 nSOC channel complex in dendritic mushroom spines is a new therapeutic target for treatment of memory loss in aging and AD and that NSN21778 is a potential candidate molecule for therapeutic intervention in brain aging and AD.Mushroom dendritic spine structures are essential for memory storage.  In the previous studies we suggested that the loss of mushroom spines may explain memory defects in aging and Alzheimer’s disease (AD).  We further demonstrated that the stability of mushroom spines depends on STIM2-mediated neuronal store operated calcium (Ca2+) influx (nSOC) pathway which is compromised in AD mouse models, in aging neurons and in sporadic AD patients (Sun at al,  2014, Neuron,  vol 82, pp 79-93;  Zhang at al,  J. Neuroscience, vol 35, pp 13275-13286;  Popugaeva at al, 2015, Molecular Neurodegeneration, 10:37).    The molecular identity of channel encoding SOC influx in spines remains unknown.   We now demonstrate that TRPC6 and Orai2 channels form a STIM2-regulated nSOC Ca2+ channel complex in hippocampal mushroom spines.   We further demonstrate that a known TRPC6 activator hyperforin and a novel nSOC positive modulator NSN21778 can stimulate activity of nSOC pathway in the spines and rescue mushroom spine loss in both presenilin and APP knock-in mouse models of AD. We further show that NSN21778 rescues hippocampal long-term potentiation impairment in APP knock-in mouse model.  We conclude that STIM2-regulated TRPC6/Orai2 nSOC channel complex in dendritic mushroom spines is a new therapeutic target for treatment of memory loss in aging and AD and that NSN21778 is a potential candidate molecule for therapeutic intervention in brain aging and AD.