Biology subjects

Stokin, G. B.

Publications and source records attributed to Stokin, G. B..

3 recordsLinked to original sources

bioRxiv2023

Amyloid precursor protein induces reactive astrogliosis

We present in vitro and in vivo evidence demonstrating that Amyloid Precursor Protein (APP) acts as an essential instigator of reactive astrogliosis. Cell-specific overexpression of APP in cultured astrocytes led to remodelling of the intermediate filament network, enhancement of cytokine production and activation of cellular programs centred around the interferon (IFN) pathway, all signs of reactive astrogliosis. Conversely, APP deletion in cultured astrocytes abrogated remodelling of the intermediate filament network and blunted expression of IFN stimulated gene (ISG) products in response to lipopolysaccharide (LPS). Following traumatic brain injury (TBI), mouse reactive astrocytes also exhibited an association between APP and IFN, while APP deletion curbed the increase in glial fibrillary acidic protein (GFAP) observed canonically in astrocytes in response to TBI. Thus, APP represents a molecular inducer and regulator of reactive astrogliosis.

neuroscience↗

bioRxiv2022

Familial Alzheimer disease mutation undermines axonal transportby enhancing dynactin recruitment to the APP motor assemblies

Experiments in flies, mice and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimers disease (AD), however, the underlying mechanisms remain unknown1,2. We report that the Swedish familial AD (FAD) mutation perturbs fast anterograde axonal transport of the amyloid precursor protein (APP) by altering directionality of its movement. APP thus spends more time in retrograde movement and accumulates in the soma. We found that the Swedish mutation enhances recruitment of dynactin 1 to the APP transport assemblies. Given that dynactin 1 activates the retrograde motor dynein3, this hampers physiological anterograde axonal transport of APP. We last show that the Swedish mutation perturbs also the axonal transport of early endosomes, which rely on the same molecular motors as APP. Our findings reveal extensive impairment of the axonal transport pathways by a FAD mutation, which reflects dysregulation of the cargo motor assemblies.

neuroscience↗

bioRxiv2022

Unraveling axonal mechanisms of traumatic brain injury

Axonal swellings (AS) are the neuropathological hallmark of axonal injury in several disorders from trauma to neurodegeneration. Current evidence proposes a role of perturbed Ca2+ homeostasis in AS formation, involving impaired axonal transport and focal distension of the axons. Mechanisms of AS formation, in particular moments following injury, however, remain unknown. Here we show that AS form independently from intra-axonal Ca2+ changes, which are required primarily for the persistence of AS in time. We further show that the majority of axonal proteins undergoing de/phosphorylation immediately following injury belong to the cytoskeleton. This correlates with an increase in the distance of the actin/spectrin periodic rings and with microtubule tracks remodeling within AS. Observed cytoskeletal rearrangements support axonal transport without major interruptions. Our results demonstrate that the earliest axonal response to injury consists in physiological adaptations of axonal structure to preserve function rather than in immediate pathological events signaling axonal destruction.

neuroscience↗