Chronic Intermittent Hypoxia Induces Robust Astrogliosis in an Alzheimer’s Disease-Relevant Mouse Model

Abstract

Sleep disturbances are a common early symptom of neurodegenerative diseases, including Alzheimer's disease (AD) and other age-related dementias, and emerging evidence suggests that poor sleep may be an important contributor to development of amyloid pathology. Of the causes of sleep disturbances, it is estimated that 10%-20% of adults in the United States have sleepdisordered breathing (SDB) disorder, with obstructive sleep apnea accounting for the majority of the SBD cases. The clinical and epidemiological data clearly support a link between sleep apnea and AD; yet, almost no experimental research is available exploring the mechanisms associated with this correlative link. Therefore, we exposed an AD-relevant mouse model (APP/PS1 KI) to chronic intermittent hypoxia (an experimental model of sleep apnea) to begin to describe one of the potential mechanisms by which SDB could increase the risk of dementia. Previous studies have found that astrogliosis is a contributor to neuropathology in models of chronic intermittent hypoxia (IH) and AD; therefore, we hypothesized that a reactive astrocyte response might be a contributing mechanism in the neuroinflammation associated with sleep apnea. To test this hypothesis, 10-11-month-old wild type (WT) and APP/PS1 KI mice were exposed to 10 hours of IH, daily for four weeks. At the end of four weeks brains were analyzed from amyloid burden and astrogliosis. No effect was found for chronic IH exposure on amyloid-beta levels or plaque load in the APP/PS1 KI mice. A significant increase in GFAP staining was found in the APP/PS1 KI mice following chronic IH exposure, but not in the WT mice. Profiling of genes associated with different phenotypes of astrocyte activation identified GFAP, CXCL10, and Ggta1 as significant responses activated in the APP/PS1 KI mice exposed to chronic IH.

Involvement of Hepcidin in Cognitive Damage Induced by Chronic Intermittent Hypoxia in Mice

“…Astrocytes are also the main glia cells which produce and secrete hepcidin [13,30]. Studies have demonstrated that CIH exposure could further induce the activation of astrocytes in APP/PS1 mice and exacerbate the pathogenesis of disease [3]. Coincidentally, results of the present study indicated the increased astrocyte activation during CIH exposure, and the expression level of hepcidin also increased concomitantly (Figure 1).…”

“…Epidemiological study has demonstrated that the number of OSA patients worldwide has exceeded 9.36 million, and it is becoming a serious global problem [2]. OSA has been identified as an early risk factor for developing neurodegenerative disease, such as Alzheimer's disease (AD) [1,3]. Clinical studies have shown that OSA could accelerate the progression of AD by increasing the formation and accumulation of Aβ 42 in the cerebrospinal fluid (CSF) [4,5].…”

Sleep Apnea Syndrome in an Elderly Population Admitted to a Geriatric Unit: Prevalence and Effect on Cognitive Function

“…It is unclear why, unlike previous literature, AHI rather than oxygen desaturation was associated with cognitive deficit in our cohort, though it could be due to the different manifestations in SAS in the elderly population and in the general population (Al Lawati et al, 2009;Heinzer et al, 2015). The relationship between intermittent hypoxia and cognition remain complex, however, and animal studies have suggested that intermittent hypoxia may not directly impair brain structure (Jorba et al, 2017), but may play a role in the etiology of Alzheimer's Disease (Shiota et al, 2013;Menal et al, 2018;Macheda et al, 2019). Nevertheless, fragmented sleep and excessive daytime sleepiness have been shown to modify the relationship between AHI and several co-morbidities (Nena et al, 2012;Ren et al, 2016) and could contribute to cognitive decline in SAS patients (Zhou et al, 2016).…”

Prevention and Management of Delirium in the Intensive Care Unit

“…[93][94][95] Chronic intermittent hypoxia can induce neurodegenerative changes to brain tissue that may predispose patients to delirium. 96,97 Finally, research has shown that the presence of plasma tryptophan, 86,98 a precursor of the neurotransmitter serotonin, and inflammatory biomarkers (procalcitonin and C-reactive protein) 99-101 may be linked with the development of delirium. The mechanism behind C-reactive protein and delirium appears to be associated with a disruption in the BBB due to generation of reactive oxygen species.…”