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Upregulated Ca2+ release from the endoplasmic reticulum leads to impaired presynaptic function in Alzheimer’s disease

Temitope Adeoye, Syed I Shah, Angelo Demuro, David A Rabson, View ORCID ProfileGhanim Ullah
doi: https://doi.org/10.1101/2022.04.21.489060
Temitope Adeoye
1Department of Physics, University of South Florida, Tampa, FL 33620
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Syed I Shah
1Department of Physics, University of South Florida, Tampa, FL 33620
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Angelo Demuro
2Department of Neurobiology and Behaviour University of California, Irvine, CA 92697
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David A Rabson
1Department of Physics, University of South Florida, Tampa, FL 33620
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Ghanim Ullah
1Department of Physics, University of South Florida, Tampa, FL 33620
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  • ORCID record for Ghanim Ullah
  • For correspondence: gullah@usf.edu
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Abstract

Neurotransmitter release from presynaptic terminals is primarily regulated by rapid Ca2+ influx through membrane-resident voltage-gated Ca2+ channels (VGCCs). Also, accumulating evidence indicates that the endoplasmic reticulum (ER) is extensively present in axonal terminals of neurons and plays a modulatory role in synaptic transmission by regulating Ca2+ levels. Alzheimer’s disease (AD) is marked by enhanced Ca2+ release from the ER and downregulation of Ca2+ buffering proteins. However, the precise consequence of impaired Ca2+ signalling within the vicinity of VGCCs (active zone (AZ)) on exocytosis is poorly understood. Here, we perform in-silico experiments of intracellular Ca2+ signalling and exocytosis in a detailed biophysical model of hippocampal synapses to investigate the effect of aberrant Ca2+ signalling on neurotransmitter release in AD. Our model predicts that enhanced Ca2+ release from the ER increases the probability of neurotransmitter release in AD. Moreover, over very short timescales (30-60 msec), the model exhibits activity-dependent and enhanced short-term plasticity in AD, indicating neuronal hyperactivity—a hallmark of the disease. Similar to previous observations in AD animal models, our model reveals that during prolonged stimulation (~450 msec), pathological Ca2+ signalling increases depression and desynchronization with stimulus, causing affected synapses to operate unreliably. Overall, our work provides direct evidence in support of a crucial role played by altered Ca2+ homeostasis mediated by intracellular stores in AD.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 22, 2022.
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Upregulated Ca2+ release from the endoplasmic reticulum leads to impaired presynaptic function in Alzheimer’s disease
Temitope Adeoye, Syed I Shah, Angelo Demuro, David A Rabson, Ghanim Ullah
bioRxiv 2022.04.21.489060; doi: https://doi.org/10.1101/2022.04.21.489060
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Upregulated Ca2+ release from the endoplasmic reticulum leads to impaired presynaptic function in Alzheimer’s disease
Temitope Adeoye, Syed I Shah, Angelo Demuro, David A Rabson, Ghanim Ullah
bioRxiv 2022.04.21.489060; doi: https://doi.org/10.1101/2022.04.21.489060

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