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Neuropathology induced by sterol glucosides in mice Tabata, Rena Christina

Abstract

Sterol glucosides are a family of compounds characterized by a carbohydrate unit bound to a tetracyclic carbon chain. They are found in high concentrations in cycad seeds which have been linked to the etiology of amyotrophic lateral scierosis-parkinsonism dementia complex (ALS-PDC). The neurotoxicities of the three main cycad sterol glucosides, campesterol β-D-glucoside, stigmasterol β-Dglucoside (SG), and β-sitosterol β-D-glucoside (BSSG) have been demonstrated previously in vitro. In the present study, we demonstrate that SC and BSSG exert neurotoxic effects in vivo. An outbred strain of mice was fed BSSG or SG (1000 μg daily) for a period of 15 wk and sacrificed immediately after or at 17 wk later. A battery of behavioural tests, including rotarod, wirehang, modified leg extension reflex test, treadmill, and open field were used to monitor behavioural disturbances. An array of histological measures was also conducted to assess the cellular impact of BSSG and SG. Behavioural test performance scores revealed that BSSG and SG impaired spinal reflexes and decreased overall movement. In addition to this, SC was found to impair motor coordination and strength. Also, ventral plane videography of performance on a treadmill and open field tests indicated that SG-exposed animals were more anxious and tended to drag and shuffle their limbs during forward movement. The cellular impact of dietary BSSG and SG exposures were also different. Animals exposed to each of the sterol glucosides showed an upregulation of activating transcription factor-3 and an increase in the incidence of phosphorylation of junser⁷³ in response to stress. However, BSSG-exposure induced neurodegeneration that primarily targeted large motor neurons whereas SC impacted a more diverse motor neuron population, including large and small motor neurons. Exposure to each of the sterol glucoside caused intense proliferation of astrocytes and microglia as well as a depletion of dopamine levels in the substantia nigra and striatum. Lastly, SG-exposure induced the pathological aggregation of either tau or transactivating DNA binding protein-43 in some animals. The insights gained from this study will be useful for elucidating the pathogenesis of ALS-PDC and related disorders.

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