Neurodegenerative diseases cause severe impairments in cognitive and motor function. With an increasing aging population and the onset of these diseases between 50-70 years, the consequences are bound to be devastating. While age and longevity are the main risk factors for neurodegenerative diseases, sex is also an important risk factor. Sex is multifaceted, encompassing sex chromosome complement, sex hormones (estrogens and androgens), and sex hormone receptors. Sex hormone receptors can induce various signaling cascades, ranging from genomic transcription to intracellular signaling pathways that are dependent on the health of the cell. Oxidative stress, associated with aging, can impact the health of the cell. Sex hormones can be neuroprotective under low oxidative stress conditions but not in high oxidative stress conditions. An understudied sex hormone receptor that can induce activation of oxidative stress signaling is the membrane androgen receptor (mAR). mAR can mediate NADPH oxidase (NOX) generated oxidative stress that is associated with several neurodegenerative diseases, such as Alzheimer’s disease. Further complicating this is that aging can alter sex hormone signaling. Prior to menopause, women experience more estrogens than androgens. During menopause, this sex hormone profile switches in women due to the dramatic ovarian loss of 17β-estradiol with maintained ovarian androgen (testosterone, androstenedione) production. Indeed, aging men have higher estrogens than aging women due to aromatization of androgens to estrogens. Therefore, higher activation of mAR-NOX signaling could occur in menopausal women compared to aged men, mediating the observed sex differences. Understanding these signaling cascades could provide therapeutic targets for neurodegenerative diseases.
Minor changes (~0.1 m/s) in human gait speed are predictive of various measures of decline and can be used to identify at-risk individuals prior to further decline. These associations are possible due to an abundance of human clinical research. However, age-related gait changes are not well defined in rodents, even though rodents are used as the primary pre-clinical model for many disease states as well as aging research. Our study investigated the usefulness of a novel automated system, the CatWalk™ XT, to measure age-related differences in gait. Furthermore, age-related functional declines have been associated with decreases in the reduced to oxidized glutathione ratio leading to a pro-oxidizing cellular shift. Therefore the secondary aim of this study was to determine whether chronic glutathione deficiency led to exacerbated age-associated impairments. Groups of male and female wild-type (gclm+/+) and knock-out (gclm-/-) mice aged 4, 10 and 17 months were tested on the CatWalk and gait measurements recorded. Similar age-related declines in all measures of gait were observed in both males and females, and chronic glutathione depletion was associated with some delays in age-related declines, which were further exacerbated. In conclusion, the CatWalk is a useful tool to assess gait changes with age, and further studies will be required to identify the potential compensating mechanisms underlying the effects observed with the chronic glutathione depletion.
Lack of medications or procedures available for reversing or modifying the progression of Alzheimer's disease (AD) has led to heightened search for alternatives. This is in the face of over 400 failed clinical trials that have targeted specific pathways in the pathophysiology of the disease including β‐amyloid, tau and inflammation. Based on these failures and the complexity of AD, examining alternative treatments that target several disease‐related pathways in parallel is of utmost importance. Oxidative stress and neuroinflammation have been identified as major factors involved in the pathogenesis of AD, therefore a treatment that has the potential to reduce these two factors could decrease AD pathologies and improve brain function. Hyperbaric oxygen therapy (HBOT) has been used for the past 50 years for decompression sickness, thermal burns, and wound healing among others. Recently, HBOT has been shown as a promising treatment for conditions such as traumatic brain injury and stroke, and improved cognitive function while reducing inflammation and plaque deposition in the 3xTg mouse model of AD. In a model of atherosclerosis, HBOT reduced systemic inflammation and induced antioxidant enzymes. More recently, HBOT treatment improved cognitive impairment in 42 AD patients. The objective of this experiment was to further characterize and optimize the use of HBOT as a novel avenue to treat AD. It was hypothesized that HBOT will reverse cognitive impairments associated with AD by reducing neuroinflammation and boosting antioxidant defenses. Male and female 5xFAD mice together with age‐matched control (non‐carriers) were divided into 4 groups: control‐HBOT, control +HBOT, 5xFAD‐HBOT and 5xFAD+HBOT. At 9 months, HBOT was started (consisting of increasing the O2 pressure to 2ATM and maintaining it for 90 min). A battery of behavioral tests assessing motor and cognitive function was started 1 month into the treatment. The 5xFAD mice exhibited poorer spatial and associative learning and impaired cognitive flexibility. These deficits were mostly restored by HBOT, especially in females on all three tests. Female 5xFAD mice exhibited hypoactivity, which was reversed to normal activity levels by HBOT. While these results are preliminary, they do support HBOT as a viable option for managing AD. It sets the stage to look into the redox status and molecular components/pathway of parts of the brain that are adversely affected in AD. Identification of these targets and pathway could lead to potential development of novel therapeutic approaches in AD.
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