Effects of pre-existing olfactory inflammation on Parkinson's disease related pathology following diffuse traumatic brain injury.

Research overview

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Parkinson's Disease (PD) is a multifactorial neurodegenerative disorder, characterised by the stereotypical aggregation and spread of α-synuclein, with the olfactory system representing an early site of pathology. Risk factors for PD include traumatic brain injury (TBI) and exposure to environmental agents that induce olfactory inflammation, such as toxins and pathogens. However, despite these associations, the absolute risk of developing PD following such exposures remains low, suggesting that these factors may interact to modify vulnerability to PD development. This study aimed to investigate whether TBI occurring in the setting of pre-existing olfactory pathology induced by lipopolysaccharide (LPS) modifies molecular and behavioural outcomes relevant to PD in Sprague Dawley rats. Following confirmation that a single high-dose intranasal LPS exposure (100 μg) increased phosphorylated α-synuclein in the olfactory bulb at 7-days post-exposure, we examined its interaction with TBI delivered at this time-point. By 3-months post-injury, intranasal LPS alone induced persistent olfactory bulb inflammation, while TBI in isolation elicited chronic microglial morphological changes in both the olfactory system and substantia nigra (SN), together with a reduction in TH-positive neurons in the SN. Nevertheless, these neuroinflammatory changes within PD-relevant regions showed only limited synergistic effects, with prior LPS exposure increasing phosphorylated-α-synuclein in the SN of injured, but not sham, animals. However, there was no change in microglial morphological appearance or behavioural measures associated with prodromal PD, including olfaction, cognition, gastrointestinal function, and motor performance. This provides a framework for future studies investigating how multiple interacting PD risk factors may cumulatively influence vulnerability to PD-relevant pathology over time.

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