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Unraveling Aβ-Mediated Multi-Pathway Calcium Dynamics in Astrocytes: Implications for Alzheimer’s Disease Treatment From Simulations

ABSTRACT: The accumulation of amyloid β peptide (Aβ) in the brain is hypothesized to be the major factor driving Alzheimer’s disease (AD) pathogenesis. Mounting evidence suggests that astrocytes are the primary target of Aβ neurotoxicity. Aβ is known to interfere with multiple calcium fluxes, thus disrupting the calcium homeostasis regulation of astrocytes, which are likely to produce calcium oscillations. Ca2+ dyshomeostasis has been observed to precede the appearance of clinical symptoms of AD; however, it is experimentally very difficult to investigate the interactions of many mechanisms. Given that Ca2+ disruption is ubiquitously involved in AD progression, it is likely that focusing on Ca2+ dysregulation may serve as a potential therapeutic approach to preventing or treating AD, while current hypotheses concerning AD have so far failed to yield curable therapies. For this purpose, we derive and investigate a concise mathematical model for Aβ-mediated multi-pathway astrocytic intracellular Ca2+ dynamics. This model accounts for how Aβ affects various fluxes contributions through voltage-gated calcium channels, Aβ-formed channels and ryanodine receptors. Bifurcation analysis of Aβ level, which reflected the corresponding progression of the disease, revealed that Aβ significantly induced the increasing [Ca2+]i and frequency of calcium oscillations. The influence of inositol 1,4,5-trisphosphate production (IP3) is also investigated in the presence of Aβ as well as the impact of changes in resting membrane potential. In turn, the Ca2+ flux can be considerably changed by exerting specific interventions, such as ion channel blockers or receptor antagonists. By doing so, a “combination therapy” targeting multiple pathways simultaneously has finally been demonstrated to be more effective. This study helps to better understand the effect of Aβ, and our findings provide new insight into the treatment of AD.

SUBMITTER: Liu L

PROVIDER: S-EPMC8581622 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Recent years have witnessed an increasing interest in neuron-glia communication. This interest stems from the realization that glia participate in cognitive functions and information processing and are involved in many brain disorders and neurodegenerative diseases. An important process in neuron-glia communications is astrocyte encoding of synaptic information transfer-the modulation of intracellular calcium (Ca(2+)) dynamics in astrocytes in response to synaptic activity. Here, we derive and investigate a concise mathematical model for glutamate-induced astrocytic intracellular Ca(2+) dynamics that captures the essential biochemical features of the regulatory pathway of inositol 1,4,5-trisphosphate (IP(3)). Starting from the well-known two-variable (intracellular Ca(2+) and inactive IP(3) receptors) Li-Rinzel model for calcium-induced calcium release, we incorporate the regulation of IP(3) production and phosphorylation. Doing so, we extend it to a three-variable model (which we refer to as the ChI model) that could account for Ca(2+) oscillations with endogenous IP(3) metabolism. This ChI model is then further extended into the G-ChI model to include regulation of IP(3) production by external glutamate signals. Compared with previous similar models, our three-variable models include a more realistic description of IP(3) production and degradation pathways, lumping together their essential nonlinearities within a concise formulation. Using bifurcation analysis and time simulations, we demonstrate the existence of new putative dynamical features. The cross-couplings between IP(3) and Ca(2+) pathways endow the system with self-consistent oscillatory properties and favor mixed frequency-amplitude encoding modes over pure amplitude-modulation ones. These and additional results of our model are in general agreement with available experimental data and may have important implications for the role of astrocytes in the synaptic transfer of information.

Project description:Calcium ion regulation plays a crucial role in maintaining neuronal functions such as neurotransmitter release and synaptic plasticity. Copper (Cu2+ ) coordination to amyloid-β (Aβ) has accelerated Aβ1-42 aggregation that can trigger calcium dysregulation by enhancing the influx of calcium ions by extensive perturbing integrity of the membranes. Aβ1-42 aggregation, calcium dysregulation, and membrane damage are Alzheimer disease (AD) implications. To gain a detail of calcium ions' role in the full-length Aβ1-42 and Aβ1-42 -Cu2+ monomers contact, the cellular membrane before their aggregation to elucidate the neurotoxicity mechanism, we carried out 2.5 μs extensive molecular dynamics simulation (MD) to rigorous explorations of the intriguing feature of the Aβ1-42 and Aβ1-42 -Cu2+ interaction with the dimyristoylphosphatidylcholine (DMPC) bilayer in the presence of calcium ions. The outcome of the results compared to the same simulations without calcium ions. We surprisingly noted robust binding energies between the Aβ1-42 and membrane observed in simulations containing without calcium ions and is two and a half fold lesser in the simulation with calcium ions. Therefore, in the case of the absence of calcium ions, N-terminal residues of Aβ1-42 deeply penetrate from the surface to the center of the bilayer; in contrast to calcium ions presence, the N- and C-terminal residues are involved only in surface contacts through binding phosphate moieties. On the other hand, Aβ1-42 -Cu2+ actively participated in surface bilayer contacts in the absence of calcium ions. These contacts are prevented by forming a calcium bridge between Aβ1-42 -Cu2+ and the DMPC bilayer in the case of calcium ions presence. In a nutshell, Calcium ions do not allow Aβ1-42 penetration into the membranes nor contact of Aβ1-42 -Cu2+ with the membranes. These pieces of information imply that the calcium ions mediate the membrane perturbation via the monomer interactions but do not damage the membrane; they agree with the western blot experimental results of a higher concentration of calcium ions inhibit the membrane pore formation by Aβ peptides.

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Unraveling Aβ-Mediated Multi-Pathway Calcium Dynamics in Astrocytes: Implications for Alzheimer’s Disease Treatment From Simulations

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