Deep Learning to Decipher the Progression and Morphology of Axonal Degeneration

Abstract

Axonal degeneration (AxD) is a pathological hallmark of many neurodegenerative diseases. Deciphering the morphological patterns of AxD will help to understand the underlying mechanisms and develop effective therapies. Here, we evaluated the progression of AxD in cortical neurons using a novel microfluidic device together with a deep learning tool that we developed for the enhanced-throughput analysis of AxD on microscopic images. The trained convolutional neural network (CNN) sensitively and specifically segmented the features of AxD including axons, axonal swellings, and axonal fragments. Its performance exceeded that of the human evaluators. In an in vitro model of AxD in hemorrhagic stroke induced by the hemolysis product hemin, we detected a time-dependent degeneration of axons leading to a decrease in axon area, while axonal swelling and fragment areas increased. Axonal swellings preceded axon fragmentation, suggesting that swellings may be reliable predictors of AxD. Using a recurrent neural network (RNN), we identified four morphological patterns of AxD (granular, retraction, swelling, and transport degeneration). These findings indicate a morphological heterogeneity of AxD in hemorrhagic stroke. Our EntireAxon platform enables the systematic analysis of axons and AxD in time-lapse microscopy and unravels a so-far unknown intricacy in which AxD can occur in a disease context.

Mesenchymal Stem Cell Application and Its Therapeutic Mechanisms in Intracerebral Hemorrhage

“… Zille et al (2017) have verified that the hemin and hemoglobin-induced toxic mediators from lysed blood after ICH participate in the death of primary cortical neurons through ferroptosis and necroptosis, rather than caspase-dependent apoptosis or autophagy in vitro and in vivo . Moreover, Palumbo et al (2021) observed a time-dependent morphological degeneration of axons in hemin-induced primary cortical neurons, resulting in a declination of the axon area and enhancement of axonal swelling and fragment areas depending on a novel microfluidic device and a deep learning tool on microscopy. Hemorrhages in the internal capsule block the axonal transport to induce axonal dysfunction closely associated with an early decline of motor performance in mice with ICH ( Hijioka et al, 2016 ).…”

Rescue of the increased susceptibility to Mild Chronic Oxidative Stress of iNeurons carrying the MAPT Chromosome 17q21.3 H1/H1 risk allele by FDA-approved compounds

“…During the course of the neurotoxicity assay, we noticed increased signs of axonal degeneration similar to those observed in tauopathies before cell death (Kneynsberg et al ., 2017). Blebs, also referred to in the literature as swellings, beadings, spheroids or varicosities, (Luo and O’Leary, 2005; Datar et al ., 2019; Yong et al ., 2019; Palumbo et al ., 2021) were observed at day 8 neuronal axons of H1/H1 haplotype, depleted for 5 weeks of AO, just before the neuronal cell death. These blebs started to develop at sub-regions of wells and propagated to other regions within 24 hours.…”

Downregulation of CDK5 signaling in the dorsal striatum alters striatal microcircuits implicating the association of pathologies with circadian behavior in mice

“…Brain functions are mediated by multiple neuronal activities involving highly elaborate and complex synaptic connections. Neurons need to transport organelles, proteins, and lipids from the soma to the axon and dendrites and back again to maintain a normal functional state [ 49 , 50 ]. Microtubules act as conduits for both anterograde and retrograde transport of molecules [ 51 , 52 ].…”