Effects of growth hormone-releasing hormone on sleep and brain interstitial fluid amyloid-β in an APP transgenic mouse model

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by impairment of cognitive function, extracellular amyloid plaques, intracellular neurofibrillary tangles, and synaptic and neuronal loss. There is substantial evidence that the aggregation of amyloid beta (A beta) in the brain plays a key role in the pathogenesis of AD and that A beta aggregation is a concentration dependent process. Recently, it was found that A beta levels in the brain interstitial fluid (ISF) are regulated by the sleep-wake cycle in both humans and mice; ISF A beta is higher during wakefulness and lower during sleep. Intracerebroventricular infusion of orexin increased wakefulness and ISF A beta levels, and chronic sleep deprivation significantly increased A beta plague formation in amyloid precursor protein transgenic (APP) mice. Growth hormone-releasing hormone (GHRH) is a well-documented sleep regulatory substance which promotes non-rapid eye movement sleep. GHRHR(lit/lit) mice that lack functional GHRH receptor have shorter sleep duration and longer wakefulness during light periods. The current study was undertaken to determine whether manipulating sleep by interfering with GHRH signaling affects brain ISF A beta levels in APPswe/PS1 Delta E9 (PSIAPP) transgenic mice that overexpress mutant forms of APP and PSENI that cause autosomal dominant AD. We found that intraperitoneal injection of GHRH at dark onset increased sleep and decreased ISF A beta and that delivery of a GHRH antagonist via reverse-microdialysis suppressed sleep and increased ISF A beta. The diurnal fluctuation of ISF A beta in PS1APP/GHRHR(lit/lit) mice was significantly smaller than that in PSIAPP/GHRHR(lit/+) mice. However despite decreased sleep in GHRHR deficient mice, this was not associated with an increase in A beta accumulation later in life. One of several possibilities for the finding is the fact that GHRHR deficient mice have GHRH-dependent but sleep-independent factors which protect against A beta deposition. (C) 2014 Elsevier Inc. All rights reserved.