UNDERSTANDING THE ROLE OF RAB10 IN NEURONAL RESILIENCE
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Date
2023-12-08
Access
2025-12-01
Authors
Bunner, Wyatt P
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Publisher
East Carolina University
Abstract
Neuroresilience refers to the remarkable capacity of the brain to maintain its normal functioning and safeguard against cognitive decline even in the face of stress or trauma. The exploration of genes and pathways that play a role in mediating neuroresilience has garnered significant attention in recent years with the small GTPase known as Rab10 emerging as one of significant note. Functioning as a "resilience factor," a rare variant of Rab10 that has reduced activity has been found to confer resilience against Alzheimer's disease (AD). The primary objectives of this dissertation were to shed new light on the intricate functions of Rab10 and to contribute to the identification of novel biomarkers for neuroresilience, as well as therapeutic targets for the treatment of neurodegenerative disorders.
Nanostring nCounter platform was utilized for the analysis of 880 genes involved in neurodegeneration. This showed that Rab10+/− mice have increased activation of pathways associated with neuronal metabolism, structural integrity, neurotransmission, and neuroplasticity compared with their Rab10+/+ littermates. Lower activation was observed for pathways involved in neuroinflammation and aging. We identified and validated several differentially expressed genes (DEGs), including Stx2, Stx1b, Vegfa, and Lrrc25 (downregulated) and Prkaa2, Syt4, and Grin2d (upregulated). Behavioral testing showed that Rab10+/− mice perform better in a hippocampal-dependent spatial task (object in place test), while their performance in a classical conditioning task (trace eyeblink classical conditioning, TECC) was significantly impaired.
We also identified different central and peripheral immune targets that Rab10 may help grant to combat neurodegeneration. Of note, basal microglia activation is significantly less in Rab10+/−. Peripheral immune profiling of Rab10+/− mice showed reduced Natural Killer cells and a different phenotype distribution of CD8+ and CD4+ positive T-cells. Finally, Rab10 may provide a neuroprotective role via its ability to lower the production of inflammatory cytokines such as interleukin-1β, tumor necrosis factor-alpha, and interferon gamma. Further work is needed to evaluate whether any of these changes mediates the behavioral phenotypes and the resilience that Rab10 confers. We conclude that Rab10+/− mice described here can be a valuable tool to study the mechanisms of resilience in AD model mice and to identify novel therapeutical targets to prevent cognitive decline associated with normal and pathologic aging.