Lentiviral vector delivery of orexin gene to study potential role of orexin and sleep modulation in the pathogenesis of alzheimer’s disease

초록

Aggregation of amyloid-β (Aβ) with aging is an upstream pathologic event in Alzheimer’s disease (AD) pathogenesis. Aβ accumulation and disruption in the sleep-wake cycle are known to have a reciprocal relationship. Orexins (hypocretins) initiate and maintain wakefulness and loss of orexin-producing neurons causes narcolepsy. In this chapter, we described whether lentiviral vector-driven orexin release or secondary changes in sleep via orexin modulation affects Aβ pathology. Amyloid precursor protein (APP)/PS1 transgenic mice in which the orexin gene is knocked out showed a marked decrease in the amount of Aβ pathology in the brain with an increase in sleep time. Focal overexpression of orexin in the hippocampus in APP/PS1 mice did not alter the total amount of sleep/wakefulness and the amount of Aβ pathology. In contrast, increasing wakefulness by rescue of orexinergic neurons in APP/PS1 mice lacking orexin increased the amount of Aβ pathology in the brain. Taken together, modulation of orexin via lentiviral vectors and its potential effects on sleep appear to modulate Aβ pathology in the brain. © 2018 Elsevier Inc. All rights reserved.

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