Modeling the neuron as a nanocommunication system to identify spatiotemporal molecular events in neurodegenerative disease

Abstract

AimIn tauopathies such as Alzheimer’s disease (AD), molecular changes spanning multiple subcellular compartments of the neuron contribute to neurodegeneration and altered axonal signaling. Computational modeling of end-to-end linked events benefit mechanistic analysis and can be informative to understand disease progression and accelerate development of effective therapies. In the calcium-amyloid beta model of AD, calcium ions that are an important regulator of neuronal function undergo dysregulated homeostasis that disrupts cargo loading for neurotrophic signaling along axonal microtubules (MTs). The aim of the present study was to develop a computational model of the neuron using a layered architecture simulation that enables us to evaluate the functionalities of several interlinked components in the calcium-amyloid beta model.MethodsThe elevation of intracellular calcium levels is modeled upon binding of amyloid beta oligomers (AβOs) to calcium channels or as a result of membrane insertion of oligomeric Aβ1-42 to form pores/channels. The resulting subsequent Ca2+ disruption of dense core vesicle (DCV)-kinesin cargo loading and transport of brain-derived neurotrophic factor (BDNF) on axonal MTs are then evaluated. Our model applies published experimental data on calcium channel manipulation of DCV-BDNF and incorporates organizational complexity of the axon as bundled polar and discontinuous MTs. The interoperability simulation is based on the Institute of Electrical and Electronics Engineers standard association P1906.1 framework for nanoscale and molecular communication.ResultsOur analysis provides new spatiotemporal insights into the end-to-end signaling events linking calcium dysregulation and BDNF transport and by simulation compares the relative impact of dysregulation of calcium levels by AβO-channel interactions, oligomeric Aβ1-42 pores/channel formation, and release of calcium by internal stores. The flexible platform of our model allows continued expansion of molecular details including mechanistic and morphological parameters of axonal cytoskeleton networks as they become available to test disease and treatment predictions.ConclusionThe present model will benefit future drug studies on calcium homeostasis and dysregulation linked to measurable neural functional outcomes. The algorithms used can also link to other multiscale multi-cellular modeling platforms to fill in molecular gaps that we believe will assist in broadening and refining multiscale computational maps of neurodegeneration.

Axonal transport during injury on a theoretical axon

“…Finally, we anticipate that DyNAMO and other sub-neuronal models will also benefit the composition of larger neuronal communication models. We previously modeled the neuron as a nanoscale communication system using experimental data from multiple biological studies to understand and compare amyloid-beta toxicity and altered calcium signaling in Alzheimer's disease (Banerjee et al, 2018 ) in end-to-end events in intracellular signaling. It is anticipated that neuronal compartment models such as DyNAMO for axonopathies will advance biomedical research, analogous to models of synapses to evaluate synaptopathies for autism spectrum disorders (Chatterjee et al, 2021 ) and the spatial dendritic context of synaptic signaling (Larkum and Nevian, 2008 ; Tønnesen and Nägerl, 2016 ) in cognition and psychiatry.…”

“…A model allowing simulations of the viscoelasticity of the MT-associated protein tau, MAPT, was developed relevant to Alzheimer's disease and axonal stretch injuries (Ahmadzadeh et al, 2014(Ahmadzadeh et al, , 2015Barbier et al, 2019). Banerjee et al (2018) modeled multiple neuron compartmentalized functions as a nanoscale end-to-end communication system, enabling experimental data from multiple biological studies to be evaluated to compare amyloid-beta neurotoxicity at membranes, receptors, and internal calcium stores relevant to Alzheimer's disease. The DyNAMO theoretical axon is a significant step in providing a detailed framework that significantly expands the ability to interrogate a diverse set of parameters relevant to axonal MT injury, infrastructure perturbations, and impacts on motorbased axonal transport relevant to neurological disease (Sleigh et al, 2019).…”

Advances in the study of axon–associated vesicles

“…Similarly, in a calcium-amyloid beta model of Alzheimer’s disease, calcium isions are identified as important regulators of neuronal function. Changes in the concentration of intracellular calcium ions can disrupt the DCV-kinesin complex, impair the structure of the core vesicles in axonal transport, and damage brain-derived neurotrophic factor (BDNF) transport in axons ( Banerjee et al, 2018 ).…”

Cancer drug therapy and stochastic modeling of “nano-motors”

“…where both H (1) and H (2) are known as Hill functions, representing the fraction of occupied and free molecules Eg5 respectively, with This non-dimensional entity h (1) (x) when incorporated with the sinusoidal drift (ϱ in Equation 3) of the Kolmogorov backward equation works as a useful tool to trace the effect of the drug inhibitors on the Eg5 enzymes. This impact is demonstrated with the aid of graphical interpretation in Figure 3.…”

“…For the past few years, the fundamental principles and mechanisms of molecular motor dynamics have remained a topic of debate in the field of nanomedicine. 1,2 In recent years, mitotic catastrophe (activated during mitosis) has been employed as promising onco-suppressive therapeutic strategy. In current clinical strategies, various antimitotic cancer drugs such as vinca alkaloids, taxanes, and epothilone derivatives, targeting microtubules during cell division, have proved to be clinically most successful anticancer agents in bladder, ovarian, breast, lung, and head malignancies.…”