Aging / Alzheimer's Disease
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21674
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Browsing Aging / Alzheimer's Disease by Author "Cunningham, Rebecca"
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Item Chronic Intermittent Hypoxia Advances Hormonal Aging: Implications for Parkinson’s Related Sexual Dysfunction(2017-03-14) Schreihofer, Derek; Cunningham, Rebecca; Anderson, MarcPurpose: Chronic intermittent hypoxia (CIH) is an established model for sleep apnea and a common comorbidity in Parkinson’s disease (PD). Further, CIH is a known inducer of oxidative stress (OS), which is a key characteristic of PD and aging. Interestingly, in men both sleep apnea and PD are strongly linked with sexual dysfunction. However, it is unknown if CIH induces sexual dysfunction. Therefore, we examined the role of CIH on steroid hormones, sex behaviors, neuropeptides associated with social behaviors, and OS generation in young and old rats. Methods: Young (3-months) and old (12-months) male F344/BNF1 rats, were exposed to either mild CIH or normoxic conditions. CIH consisted of cycling oxygen levels from 21% to 10% over a span of 6 minutes during the rat’s sleep phase for a total of ten days. Sex behavioral tests were conducted to examine the influence of CIH. Specifically, the frequency and latencies of mounts, intromissions, and ejaculations were quantified. At the end of testing, plasma was collected and assayed for testosterone (T), corticosterone (C), vasopressin (AVP), oxytocin (OXY), and advanced oxidation protein products (AOPP). Results: Old rats had impaired sex behaviors compared to young rats. However, CIH induced sexual dysfunction in young rats, consistent with behaviors in old rats. Accordingly, in young rats CIH decreased T, increased C, and increased OS, as indicated by AOPP. CIH did not alter OXY and AVP in young rats. Interestingly, in old rats CIH had no effect on sexual behavior, T, C, OXY, or AVP, indicating that age may have a ceiling effect. Conclusions: Results show that mild CIH advances hormonal aging. Hormonal aging is an understudied phenomenon in PD and in sleep apnea. Therefore, PD progression may be halted by examining the influence of sleep apnea induced hormonal aging.Item Novel Androgen Receptor Protein in Brain: Implication for Parkinson's Disease(2017-03-14) Duong, Phong; Snyder, Brina; Cunningham, Rebecca; Garza-Contreras, JoObjective: Men have a two-fold increased risk for Parkinson’s disease (PD) than women. Testosterone, the major male sex hormone, can increase calcium influx and cell death in dopamine neurons via a putative membrane androgen receptor (mAR). The mAR induced calcium increase may be due to activation of Gaq protein-coupled receptor (GPCR) that is involved in calcium mobilization. Currently, the mAR remains unidentified. Recent studies only found miniscule levels of androgen receptors (AR) in the substantia nigra (SN). This low AR expression in the SN may be due to absence of full length classical AR that contains an N terminus domain (NTD), especially as these studies used an antibody targeting the AR NTD. It is possible that ARs in the SN consist of a splice variant that does not possess a NTD, such as AR45. AR45 is not able to be assayed using an NTD antibody, and thus we used a C-terminus domain (CTD) antibody. Therefore, we hypothesize that the putative mAR is the AR45 splice variant that acts through a Gaq GPCR. Materials and Methods: We examined the expression of classical full length AR and AR45 in a dopaminergic N27 cell line and rat SN. Protein expression of AR and AR45 was quantified by Western blot analysis and immunohistochemistry (IHC). We used antibodies targeting either the NTD or CTD of the AR, along with antibodies targeting Gαq, Gαs and Gαo GPCRs. To determine the association between mAR and GPCR subunits we performed co-immunoprecipitation using AR-CTD and Gaq antibodies. Results: Our results showed that the SN and the N27 cells express very low AR-NTD positive cells, indicative of low full length classical AR expression. However, both N27 cells and SN showed very high levels of AR-CTD positive cells. Furthermore, protein expression of AR-CTD was observed at 45 kDa molecular weight, which is consistent with the AR splice variant, AR45. This AR45 splice variant was found to be associated with Gaq in both N27 cells and SN. Conclusions: Our data indicates that the mAR in dopaminergic neurons is the AR45 splice variant, which is associated with a Gaq subunit. These results provide a mechanism for our prior studies wherein testosterone increased intracellular calcium levels. This is the first observation of an AR splice variant in neuronal tissue. Further characterization of this protein may provide a novel therapeutic target to slow the progression of PD in men.Item Preconditioning Underlies Testosterone’s Protective Effects Against Neurodegeneration(2017-03-14) Cunningham, Rebecca; Snyder, Brina D.Purpose: The incidence of neurodegenerative diseases (ND) such as Alzheimer’s disease and Parkinson’s disease is expected to rise over the next 40 years. Diagnosis occurs at advanced stages, and there is no cure or treatment for ND. Early identification of risk factors for ND may provide effective therapy targets. Because ND arises differently between men and women, major sex hormones may play a role. Many studies have examined the effects of estrogen, but not testosterone (T). T has been shown to be protective or damaging depending on the oxidative stress (OS) environment in cells. Sleep apnea is a comorbidity of ND, occurs more frequently in men than women, and is associated with decreased T. Our lab has shown that a rodent model of mild sleep apnea, chronic intermittent hypoxia (CIH), elevates OS and inflammation in brain regions associated with early-stage ND. We propose that T will protect against CIH-induced damage. Methods: Male Long-Evans rats will be divided into 3 groups: gonadectomized with cholesterol (GDX+C) or physiological T (GDX+T); gonadally intact (Intact). Afterwards, rats were exposed to eight minute cycles of alternating 10% and 21% oxygen to mimic the hypoxemia experienced by patients with sleep apnea. This cycle ran continuously for eight hours a day during the light phase for seven days. Following 7 days of CIH, behaviors associated with memory and motor function were assessed: Morris Water Maze, the novel object task, and a modified open field assay. Plasma and tissue punches from the entorhinal cortex (ETC) and substantia nigra (SN) were collected and tested for levels of OS, T, and inflammation, using Advanced Oxidative Protein Products (AOPP), ELISA, and multiplex immunoassays, respectively. Results: GDX+T had significantly more T than Intact and GDX+C, due to the CIH-induced decline in endogenous T levels in Intact rats. CIH increased OS and inflammation in GDX+C and Intact rats, whereas there was no effect in GDX+T. Rats exposed to room air were not impaired, regardless of hormone status. Conclusions: Maintenance of T is protective against OS and inflammation, key markers of ND. T loss was associated with behavioral deficits following an OS insult.