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

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.

Data‐driven stochastic model for quantifying the interplay between amyloid‐beta and calcium levels in Alzheimer's disease

“…In other words, the shift to the pathological steady state cannot be reversed by a short‐duration of $$$ {Ca}^{+2} $$$ rise, which is a characteristic of the model that makes sense given that, without this feature, every action potential would lead to an increase in $$$ A\beta $$$ as discussed in Ref. [8, 9]. Yet, because of positive feedback and the rapid development of $$$ A\beta $$$, any noise‐induced rise in $$$ A\beta $$$ will also generate an increase in $$$ {Ca}^{+2} $$$, reinforcing the initial increase in $$$ A\beta $$$ [40].…”

“…Importantly, it is possible for $$$ A\beta $$$ to bind to NMDA receptors and produce $$$ {Ca}^{+2} $$$ dyshomeostasis, which results in oxidative stress, the formation of free radicals, and the death of neurons [75]. Furthermore, $$$ A\beta $$$ can activate mGluR5 receptors, which elevates postsynaptic $$$ {Ca}^{+2} $$$ levels in the cell [8, 49]. Then, APP processing is accelerated by NMDA receptors and mGluR, which create a positive feedback loop that boosts $$$ {Ca}^{+2} $$$ influx and free radical generation [76].…”

“…Importantly, a prolonged rise in baseline $$$ {Ca}^{+2} $$$ could have an essential part in disease development by boosting the production and toxicity of $$$ A\beta $$$'s in cells with AD‐related disorders. These mutually beneficial regulations, in which $$$ A\beta $$$ promotes a $$$ {Ca}^{+2} $$$ increase, which in turn raises the level of $$$ A\beta $$$, create a positive feedback loop that is expected to create a vicious circle leading to disease development [8, 13, 40]. Inspired by this fact and using clinical data such as study data from the ADNI database (http://adni.loni.usc.edu), we developed and tested a simple novel stochastic model to predict the interplay between the $$$ A\beta $$$ and $$$ {Ca}^{+2} $$$ concentrations on AD progression in a clinical trial.…”

Aβ and Tau Regulate Microglia Metabolism via Exosomes in Alzheimer’s Disease

“…They play an important role in intercellular communication because exosomes are potential vehicles for transferring cell contents from source cells to recipient cells [ 129 ]. In AD, exosomes are related to the release of Aβ oligomer and its extracellular accumulation [ 130 , 131 , 132 , 133 ], and the accumulation of hyperphosphorylated tau [ 134 , 135 , 136 , 137 ]. In neuronal cytoplasm, APP is endocytosed and cleaved by β-secretase to form APPβ on the early endosome membrane.…”

Mathematical Models with Nonlocal Initial Conditions: An Exemplification from Quantum Mechanics

“…Starting initially from theory of elasticity, it covers today various fields theories such as nonlocal electromagnetic theory, a wealth of problems in science and engineering, including nanoscience and nanotechnology, hydrodynamictype modelling and its applications, ranging from semiconductors to challenges of climate, as well as cell engineering and other biological applications [38][39][40][41][42][43][44][45][46][47]. The latter applications include also such coupled complex systems as the human brain where nonlocal models are becoming increasingly important not only in our better understanding of information processing but also in revealing the onset and development of neurodegenerative diseases, for instance, Alzheimer's and Parkinson's to name just a few, as well as in addressing a challenge of the human behaviour in socially-interacting systems [23,[48][49][50][51]. Naturally that at a basic level of physics, much research has been centered around various versions of the Bell test, as well as scenarios with corresponding Bell inequalities, and non-classical correlations [52][53][54][55].…”