Abstract
Exosomes are nano-sized extracellular vesicles that perform a variety of biological functions linked to the pathogenesis of various neurodegenerative disorders. In Alzheimer's disease (AD), for examples, exosomes are responsible for the release of Aβ oligomers, and their extracellular accumulation, although the underpinning molecular machinery remains elusive. We propose a novel model for Alzheimer's Aβ accumulation based on Ca2+-dependent exosome release from astrocytes. Moreover, we exploit our model to assess how temperature dependence of exosome release could interact with Aβ neurotoxicity. We predict that voltage-gated Ca2+ channels (VGCCs) along with the transient-receptor potential M8 (TRPM8) channel are crucial molecular components in Alzheimer's progression.
Highlights
Protein misfolding, oligomerization, and aggregation are responsible for the initiation of pathological disorders in the brain (Soto and Pritzkow, 2018)
These spiking sequences control the dynamics of the voltage-gated Ca2+ channels (VGCCs) in the membrane (Veleticet al., 2020)
A comparative analysis has been conducted to quantify the effect of temperature and cold-sensitive neurons on the Ca2+-dependent exosomal release mediated by VGCCs and amyloid-beta in Alzheimer’s disease (AD)
Summary
Oligomerization, and aggregation are responsible for the initiation of pathological disorders in the brain (Soto and Pritzkow, 2018). In AD etiology, oligomeric Aβ can substantially affect intracellular Ca2+ homeostasis both in neurons and in astrocytes (Bezprozvanny and Mattson, 2008; Shigetomi et al, 2016), thereby potentially regulating exosome release too. The mechanism whereby this could happen and the relevant pathogenic factors are not known. The reason for this gap of knowledge is because of inherent limits in the available technology, and because the biophysical framework to account for exosomal release in the neuropil in the context of neuron-glial interactions is missing (De Pittà and Berry, 2019a). We introduce in this study, the first model for exosomal release leveraging on Aβ-dependent intracellular Ca2+ homeostasis
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