Brina Snyder

Chronic intermittent hypoxia induces oxidative stress and inflammation in brain regions associated with early‐stage neurodegeneration

Sleep apnea is a common comorbidity of neurodegenerative diseases, such as Alzheimers disease (AD) and Parkinsons disease (PD). Previous studies have shown an association between elevated oxidative stress and inflammation with severe sleep apnea. Elevated oxidative stress and inflammation are also hallmarks of neurodegenerative diseases. We show increased oxidative stress and inflammation in a manner consistent with early stages of neurodegenerative disease in an animal model of mild sleep apnea. Male rats were exposed to 7 days chronic intermittent hypoxia (CIH) for 8 h/day during the light period. Following CIH, plasma was collected and tested for circulating oxidative stress and inflammatory markers associated with proinflammatory M1 or anti‐inflammatory M2 profiles. Tissue punches from brain regions associated with different stages of neurodegenerative diseases (early stage: substantia nigra and entorhinal cortex; intermediate: hippocampus; late stage: rostral ventrolateral medulla and solitary tract nucleus) were also assayed for inflammatory markers. A subset of the samples was examined for 8‐hydroxydeoxyguanosine (8‐OHdG) expression, a marker of oxidative stress‐induced DNA damage. Our results showed increased circulating oxidative stress and inflammation. Furthermore, brain regions associated with early‐stage (but not late‐stage) AD and PD expressed oxidative stress and inflammatory profiles consistent with reported observations in preclinical neurodegenerative disease populations. These results suggest mild CIH induces key features that are characteristic of early‐stage neurodegenerative diseases and may be an effective model to investigate mechanisms contributing to oxidative stress and inflammation in those brain regions.

Presence of Androgen Receptor Variant in Neuronal Lipid Rafts

Abstract Fast, nongenomic androgen actions have been described in various cell types, including neurons. However, the receptor mediating this cell membrane–initiated rapid signaling remains unknown. This study found a putative androgen receptor splice variant in a dopaminergic N27 cell line and in several brain regions (substantia nigra pars compacta, entorhinal cortex, and hippocampus) from gonadally intact and gonadectomized (young and middle-aged) male rats. This putative splice variant protein has a molecular weight of 45 kDa and lacks an N-terminal domain, indicating it is homologous to the human AR45 splice variant. Interestingly, AR45 was highly expressed in all brain regions examined. In dopaminergic neurons, AR45 is localized to plasma membrane lipid rafts, a microdomain involved in cellular signaling. Further, AR45 protein interacts with membrane-associated G proteins Gαq and Gαo. Neither age nor hormone levels altered AR45 expression in dopaminergic neurons. These results provide the first evidence of AR45 protein expression in the brain, specifically plasma membrane lipid rafts. AR45 presence in lipid rafts indicates that it may function as a membrane androgen receptor to mediate fast, nongenomic androgen actions.

Chronic intermittent hypoxia induces hormonal and male sexual behavioral changes: Hypoxia as an advancer of aging

Sleep apnea is a common sleep disorder characterized by intermittent periods of low blood oxygen levels. The risk for sleep apnea increases with age and is more prevalent in men than women. A common comorbidity of sleep apnea includes male sexual dysfunction, but it is not clear if a causal relationship exists between sleep apnea and sexual dysfunction. Possible mechanisms that link these two disorders include oxidative stress and testosterone. Oxidative stress is elevated in clinical patients with sleep apnea and in rodents exposed to chronic intermittent hypoxia (CIH), an animal model for apnea-induced hypopnea. Further, oxidative stress levels increase with age. Therefore, age may play a role in sleep apnea-induced sexual dysfunction and oxidative stress generation. To investigate this relationship, we exposed gonadally intact 3 (young) and 12 (middle-aged) month old male F344/BN F1 hybrid male rats to 8 days of CIH, and then examined male sexual function. Plasma was used to assess circulating oxidative stress and hormone levels. Middle-aged male rats had lower testosterone levels with increased sexual dysfunction and oxidative stress, independent of CIH. However, CIH decreased testosterone levels and increased sexual dysfunction and oxidative stress only in young gonadally intact male rats, but not in gonadectomized young rats with physiological testosterone replacement. In sum, CIH had a greater impact on younger gonadally intact animals, with respect to sexual behaviors, testosterone, and oxidative stress. Our data indicate CIH mimics the effects of aging on male sexual behavior in young gonadally intact male rats.

Sex-related differences in oxidative stress and neurodegeneration

&NA; Oxidative stress has been implicated in a number of neurodegenerative diseases spanning various fields of research. Reactive oxygen species can be beneficial or harmful, depending on their concentration. High levels of reactive oxygen species can lead to oxidative stress, which is an imbalance between free radicals and antioxidants. Increased oxidative stress can result in cell loss. Interestingly, sex differences have been observed in oxidative stress generation, which may underlie sex differences observed in neurodegenerative disorders. An enhanced knowledge of the role of sex hormones on oxidative stress signaling and cell loss can yield valuable information, leading to sex‐based mechanistic approaches to neurodegeneration.

Androgens modulate chronic intermittent hypoxia effects on brain and behavior

Abstract Sleep apnea is associated with testosterone dysregulation as well as increased risk of developing neurodegenerative diseases, such as Alzheimers disease (AD) and Parkinsons disease (PD). A rodent model of the hypoxemic events of sleep apnea, chronic intermittent hypoxia (CIH), has been previously documented to impair cognitive function and elevate oxidative stress in male rats, while simultaneously decreasing testosterone. Therefore, androgens may modulate neuronal function under CIH. To investigate the role of androgens during CIH, male rats were assigned to one of four hormone groups: 1) gonadally intact, 2) gonadectomized (GDX), 3) GDX + testosterone (T) supplemented, or 4) GDX + dihydrotestosterone (DHT) supplemented. Each group was exposed to either normal room air or CIH exposure for one week, followed by memory and motor task assessments. Brain regions associated with AD and PD (entorhinal cortex, dorsal hippocampus, and substantia nigra) were examined for oxidative stress and inflammatory markers, key characteristics of AD and PD. Gonadally intact rats exhibited elevated oxidative stress due to CIH, but no significant memory and motor impairments. GDX increased memory impairments, regardless of CIH exposure. T preserved memory function and prevented detrimental CIH‐induced changes. In contrast, DHT was not protective, as evidenced by exacerbated oxidative stress under CIH. Further, CIH induced significant spatial memory impairment in rats administered DHT. These results indicate androgens can have both neuroprotective and detrimental effects under CIH, which may have clinical relevance for men with untreated sleep apnea. HighlightsTestosterone replacement prevented hypoxia induced oxidative stress damage.Dihydrotestosterone exacerbated hypoxia induced oxidative stress.Dihydrotestosterone increased hypoxia induced spatial memory impairment.Oxidative stress and inflammation was present in brains with dihydrotestosterone.

Sex differences in sleep apnea and comorbid neurodegenerative diseases

&NA; Sleep apnea is a disorder, which increasingly affects people worldwide. Whether the associated hypoxic events during sleep are central or obstructive in origin, the end result is excessive daytime sleepiness and an increased risk for several comorbidities, such as cardiovascular and neurodegenerative disorders. Sleep apnea is diagnosed more frequently in men than women, suggesting a role of sex hormones in the pathology of the disease. Furthermore, there are sex differences in the development and progression of comorbid diseases associated with sleep apnea. Therefore, treatment of sleep apnea may be clinically relevant for prevention of subsequent sex‐specific comorbid disorders. While the impact sleep apnea has on cardiovascular events has been the subject of many research studies, the role of sleep apnea in neurodegeneration is less established. Here we review known risk factors for sleep apnea and the implications of the observed sex differences in this disease. We also summarize the evidence and mechanisms for how sleep apnea may contribute to the onset of neurodegenerative disorders, such as Alzheimers disease and Parkinsons disease.