Simulation of Ca²⁺oscillations in astrocytes mediated by amyloid beta in Alzheimer’s disease

Abstract

Disruptions of astrocyte Ca 2+ signaling is important in Alzheimer's disease (AD) with the unclear mechanism of amyloid beta peptide (A). We have modified our previous computational model of spontaneous Ca 2+ oscillations in astrocytes to investigate the effects of Aon intracellular Ca 2+ dynamics. The simulation results have shown consistence with the previous experiments. Acan increase the resting concentration of intracellular Ca 2+ and change the regime of Ca 2+ oscillations by activating L-type voltage-gated calcium channels and the metabolic glutamate receptors, or by increasing ryanodine receptors sensitivity and Ca 2+ leakage, respectively. This work have provided a toolkit to study the influence of Aon intracellular Ca 2+ dynamics in AD. It is helpful for understanding the toxic role of Aduring the progression of AD. Statement of SignificanceAlzheimer's disease (AD) is the most common neurodegenerative disease with the unclear mechanism of amyloid beta peptide (A). This work have implemented a computational model to address the Ca 2+ dynamics of astrocyte mediated by Awith the four different pathways: voltage-gated calcium channels, metabotropic glutamate receptors 5, ryanodine receptor channels and membrane leak. The Ca 2+ oscillations and bifurcation diagram indicate that astrocytes exhibit ionic excitability mediated by Aβ and become the potential targets of Aneurotoxicity. We expect this shared computational model would advance the understanding of AD.

A Neuron-Glial Model of Exosomal Release in the Onset and Progression of Alzheimer's Disease

“…The effects of different values of Aβ on calcium concentrations for C c and P c without applying the induced/control signals stimulus is presented in Figure 4 . It can be seen from Figure 4 that the simulated results and trends are fully consistent with the studies reported by Gao et al ( 2020 ). It is observed that Aβ alters the membrane potential which in turn can enhance the regime of Ca 2+ oscillations and increase the stable state concentration of Ca 2+ .…”

“…By activating the L-type VGCCs and metabolic glutamate receptors, or by increasing ryanodine receptor sensitivity and Ca 2+ leakage, Aβ will increase the resting concentration of intracellular Ca 2+ and adjust the regime of Ca 2+ oscillations. The primary target of Aβ neurotoxicity is thought to be astrocytes (Gao et al, 2020 ). Astrocytes communicate with neurons and other brain cells in a functional way.…”

“…In what follows, we provide further details of our new model to address the Ca 2+ -mediated exosomal release in astrocytes mediated by Aβ through four distinct pathways: VGCCs, metabotropic glutamate receptors 5, ryanodine receptor channels, and membrane leak (Gao et al, 2020 ). The Aβ deposit and its neurotoxicity associated with AD is involved in the disruption of Ca 2+ regulation in astrocytes.…”

“…Importantly, CICR from the endoplasmic reticulum is perhaps the most well-studied Ca 2+ signaling pathway in astrocytes (De Pittà et al, 2019 ). Aβ may mediate the L-type VGCC, metabotropic glutamate receptors 5 (mGluR5), ryanodine receptor (RyR) channels, and membrane leak J in (Gao et al, 2020 ). Next, we define J SERCA which represents the flux of calcium ions from the cytosol into the endoplasmic reticulum through the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA).…”

“…In J in , J PLC , and J RyR , we also use A in , A RyR , A m to monitor the intensity of these different effects, as well as l to represent the impact of Aβ . The essential parameters used in our analysis are listed in Table 1 , they have been adopted from Gao et al ( 2020 ). The modified Ca 2+ concentrations in the cytosol, endoplasmic reticulum, and the IP 3 concentrations in the IP c cell ( P c ) are defined as follows:…”