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.
Highlights
Alzheimer’s disease (AD) is currently the most common neurodegenerative disease and is the major dementia type, which accounts for 60–70% of cases (Prince, 2015; Canter et al, 2016)
In cultures of mixed neurons and astrocytes treated with amyloid β-peptide (Aβ), astrocytes always exhibit pathological alterations before neuronal death suggesting that astrocytes appear to be the primary target of Aβ (Abramov et al, 2003)
We considered that Aβ channels and ryanodine receptors (RyRs) play a major role in the regulation of intracellular Ca2+ under the influence of Aβ, while the other two pathways have little effect
Summary
Alzheimer’s disease (AD) is currently the most common neurodegenerative disease and is the major dementia type, which accounts for 60–70% of cases (Prince, 2015; Canter et al, 2016). Astrocytes were historically considered to provide support for neurons (Carmignoto and Gómez-Gonzalo, 2010) Since they were found to be involved in many brain functions and neurodegenerative diseases such as AD and Parkinson’s disease etc., astrocytes have become a hot topic in neuroscience research over the past few decades (Tewari and Majumdar, 2012; Tewari and Parpura, 2013; Bazargani and Attwell, 2016). In cultures of mixed neurons and astrocytes treated with Aβ, astrocytes always exhibit pathological alterations before neuronal death suggesting that astrocytes appear to be the primary target of Aβ (Abramov et al, 2003) Their role as protector and housekeeper in central nervous system is universally acknowledged, Aβ impairs important supportive astrocyte functions in AD cases (Verkhratsky and Nedergaard, 2018)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
