Browsing by Subject "Neurodegenerative Diseases"
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Item Androgen Modulation of CNS During Chronic Intermittent Hypoxia(2018-05) Snyder, Brina D.; Cunningham, Rebecca L.; Barber, Robert C.; Cunningham, J. Thomas; Schreihofer, Derek A.; Planz, John V.The underlying causes of age-related neurodegenerative diseases, such as Alzheimer's disease or Parkinson's disease, are unknown. It is likely conditions which contribute to an abundance of oxidative stress throughout life renders an individual more susceptible to late-life neurodegenerative processes. Sex differences are observed in the onset and prevalence of these diseases, suggesting estrogens and androgens influence these processes. This study investigates the early role of androgens under a known oxidative stressor, sleep apnea, which frequently goes untreated in the clinical population but is but is associated with an increased risk of late-life neurodegeneration. The hypoxic events of sleep apnea can be modeled in rats by the use of chronic intermittent hypoxia (CIH). Male rats are more susceptible to hypertensive effects of CIH, a key characteristic of sleep apnea. After one week of CIH treatment, they also exhibit oxidative stress and inflammation in circulation and in brain nuclei associated with early stages of Parkinson's disease or Alzheimer's disease. This led to the hypothesis that oxidative stress and inflammation would be associated with behavior deficits and these effects are mediated by androgens. Results show that oxidative stress and inflammatory dysregulation can be prevented by testosterone, but are highly exacerbated by testosterone's non-aromatizable metabolite, dihydrotestosterone (DHT). Administration of DHT also resulted in significant memory impairments under CIH. In the central nervous system, DHT significantly altered oxidative stress and pro-inflammatory signals, which may underlie its detrimental actions in an oxidative stress environment. There was also evidence of hypothalamic-pituitary-adrenal axis dysregulation, which can influence testosterone and circadian rhythms. These findings have broad implications for clinical populations with conditions which chronically increase oxidative stress and inflammation, while at the same time alter endocrine function. Conditions, such as untreated sleep apnea, may pose a latent risk for neurodegeneration and should be addressed early to prevent later detrimental effects.Item Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry(Informa UK Limited, trading as Taylor & Francis Group, 2017-10-27) Lewczuk, Piotr; Riederer, Peter; O'Bryant, Sid E.; Verbeek, Marcel M.; Dubois, Bruno; Visser, Pieter Jelle; Jellinger, Kurt A.; Engelborghs, Sebastiaan; Ramirez, Alfredo; Parnetti, Lucilla; Jack, Clifford R.; Teunissen, Charlotte E.; Hampel, Harald; Lleó, Alberto; Jessen, Frank; Glodzik, Lidia; de Leon, Mony J.; Fagan, Anne M.; Molinuevo, José Luis; Jansen, Willemijn J.; Winblad, Bengt; Shaw, Leslie M.; Andreasson, Ulf; Otto, Markus; Mollenhauer, Brit; Wiltfang, Jens; Turner, Martin R.; Zerr, Inga; Handels, Ron; Thompson, Alexander G.; Johansson, Gunilla; Ermann, Natalia; Trojanowski, John Q.; Karaca, Ilker; Wagner, Holger; Oeckl, Patrick; van Waalwijk van Doorn, Linda; Bjerke, Maria; Kapogiannis, Dimitrios; Kuiperij, H. Bea; Farotti, Lucia; Li, Yi; Gordon, Brian A.; Epelbaum, Stéphane; Vos, Stephanie J.B.; Klijn, Catharina J.M.; Van Nostrand, William E.; Minguillon, Carolina; Schmitz, Matthias; Gallo, Carla; Lopez Mato, Andrea; Thibaut, Florence; Lista, Simone; Alcolea, Daniel; Zetterberg, Henrik; Blennow, Kaj; Kornhuber, JohannesIn the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.Item Endothelin-1 mediated decline in mitochondrial function contributes to neurodegeneration in glaucoma(2020-08) Chaphalkar, Renuka M.; Krishnamoorthy, Raghu R.; Stankowska, Dorota L.; Clark, Abbot F.; Zode, Gulab S.Glaucoma is an optic neuropathy with multifactorial etiologies, commonly associated with elevated intraocular pressure (IOP) and characterized by degeneration of the optic nerve, loss of retinal ganglion cells (RGC), cupping of optic disc and visual field deficits, which could ultimately lead to vision loss. In most cases, glaucoma is a chronic, asymptomatic and gradually progressing neurodegenerative disease, sometimes referred to as the "silent thief of sight," hence, routine eye examinations by an ophthalmologist are critical to determine if there is a likelihood of developing the disease. Elevated IOP is a primary and the only modifiable risk factor in glaucoma. Currently, reducing IOP remains the only proven treatment to delay the progression of RGC death; however, some patients continue to have neurodegenerative effects despite lowering IOP. Therefore, development of novel neuroprotection strategies as an adjunct therapy to IOP-lowering agents will provide a valuable therapeutic strategy in glaucoma. One of the promising targets for neuroprotection is the endothelin system of peptides and their receptors. The endothelin (ET) system comprises of three vasoactive peptides (ET-1, ET-2 and ET-3), which act through two types of G-protein coupled receptors, namely, ETA and ETB receptors. Originally discovered in the cardiovascular system, the diverse expression pattern of endothelin peptides and their receptors implicate their involvement in a variety of physiological processes in the body. A growing body of evidence suggests that endothelins and their receptors are associated with neurodegeneration in glaucoma. Previous studies have demonstrated that ET-1 levels are elevated in aqueous humor (AH) and plasma of glaucoma patients. Our lab previously demonstrated that in an ocular hypertension model in rats, there was an increase in ETB as well as ETA receptor expression primarily in RGCs compared to contralateral eyes. Following IOP elevation, RGC loss was significantly attenuated in the ETB receptor-deficient rats, pointing to a causative role of the ETB receptor in glaucomatous neurodegeneration. However, the precise cellular and molecular mechanisms by which ET-1 promotes neurodegeneration through its actions on the endothelin receptors are not completely understood. Previous studies have shown that ETB receptor stimulation increases the oxidative stress and production of superoxide anions, in sympathetic neurons. Several studies point to the role of mitochondrial dysfunction and oxidative stress as contributors to glaucomatous damage in animal models of glaucoma. To investigate various molecular events contributing to the ET-1 mediated RGC loss in glaucoma, we carried out RNA-seq analysis of the translatome in rat primary RGCs following ET-1 treatment. We identified several key mitochondrial and neurodegenerative gene candidates including Atp5h, Cox17, Foxo1, Moap1 and Map3k11 that were differentially expressed in the translatome by ET-1 treatment in RGCs. Based on our RNA-seq findings, we hypothesized that ET-1 causes an increase in reactive oxygen species (ROS) by acting through the ETB receptor that produces a subsequent decline in mitochondrial function and bioenergetics ultimately predisposing RGCs to cell death. To test this hypothesis, we used an in vitro approach by utilizing rat primary culture of RGCs treated with ET-1 as well as an in vivo approach by intravitreal ET-1 injections in rodents and the Morrison's model of glaucoma in rats. Our data showed that there is a significant decrease in the expression of cytochrome c oxidase 17 copper chaperone (COX17) and ATP synthase, H+ transporting, mitochondrial F0 complex, subunit D (ATP5H), both of which are critical components of the electron transport chain and oxidative phosphorylation pathway. Using a Seahorse mitostress assay, we also found a significant decline of several mitochondrial parameters following ET-1 treatment in primary RGCs, which indicated the possibility of a disruption in the mitochondrial quality control machinery. Hence, we also explored the effect of the ET-1 treatment on the mitophagy pathway, specifically in RGCs. Our findings suggest that there is a decrease in mitophagosome formation in RGCs in the Morrison ocular hypertensive model as well as in GFP-LC3 mice injected with ET-1, indicating an impairment in the mitochondrial quality control mechanism. Our studies reveal several novel candidates that could be targeted for the development of neuroprotective approaches to treat glaucoma.Item Prenatal Hypoxic Insults Impact Brain Vulnerability(2021-05) Wilson, Elizabeth N.; Cunningham, Rebecca L.; Goulopoulou, Styliani; Jones, Harlan P.; Sumien, NathalieMaternal hypoxic insults during gestation may lead to an increased risk for neurodegenerative diseases, such as Parkinson's disease (PD), in progeny. Maternal hypoxic stress is a common consequence of many late-stage prenatal stressors (e.g., preeclampsia, eclampsia, inflammation, placental abruption). It is unknown whether maternal hypoxic insults during late gestation have long-term effects on brain regions associated with PD, such as the nigrostriatal pathway. We hypothesized that late gestational maternal hypoxia would result in sustained nigrostriatal impairment in male progeny. To determine whether late-stage gestational hypoxia exposure induced PD-associated behaviors and oxidative stress in progeny, timed pregnant Long-Evans rats were exposed to five days (gestational days: 15-19) of chronic intermittent hypoxia (CIH) or room air normoxia. Progeny were tested during two developmental stages (pubertal and young adult) as late-stage gestational insults can impair the neuronal organization of the brain, which can impact pubertal and young adult functions. To examine PD-associated behavioral phenotype of motor dysfunction, we quantified fine and gross motor behaviors in an open field arena. To examine the integrity of the nigrostriatal pathway, we quantified ultrasonic vocalizations. Our results showed that maternal CIH during late gestation did not impact gross or fine motor behaviors nor circulating oxidative stress. However, maternal CIH during late gestation did impair the nigrostriatal pathway integrity during puberty and young adulthood in both male and female progeny. Long-lasting consequences of maternal CIH during late gestation was most evident in young adult male progeny. Overall, we conclude that maternal hypoxia during late gestation induced sustained nigrostriatal pathway impairment in males more than females, which may underlie the increased risk for PD in men compared to women.Item The Long-Term Neurodegenerative Effects of Repetitive Mild Traumatic Brain Injury and Treatment With Sigma-1 Receptor Agonist PRE-084(2021-05) Abad-Jacobi, Christopher; Schreihofer, Derek A.; Sumien, Nathalie; Schreihofer, Ann M.An estimated 1.6 – 3.8 million sports-related traumatic brain injuries (TBI) occur every year in the U.S. Recent retrospective studies suggest that repetitive mild TBI (rmTBI) is associated with the earlier onset of neurodegenerative diseases. Mild TBI can be hard to detect, and there are currently no widely accepted biomarkers that could aid in the diagnosis of mTBI. Further, there is currently no standard pharmacological treatment for TBI. Our previous work demonstrated neurological deficits 1 week following 20-25 rmTBI in young male mice. We hypothesized that some of these deficits would persist up to 5-15 weeks following injury and that treatment with an agonist of the Sigma-1 receptor (PRE-084) could reduce these deficits, as has been demonstrated in other neurodegenerative models. Eight-week-old male C57BK6 mice were divided into sham injury + Vehicle, rmTBI + Vehicle, and rmTBI+PRE084 groups (n=10/gp). Mice were lightly anesthetized with isoflurane and administered either PRE084 (1mg/kg sc or ip) or vehicle immediately prior to experiencing closed head-injury with rotational acceleration via a 65g weight drop 5 days a week for 5 weeks. Five (group 1) and fifteen weeks (group 2) after the final injury mice were assessed for neurological deficits. Injured mice in test 1 demonstrated significant (P<0.05) deficits in motor and vestibular-motor. Wake times were significantly increased (P<0.05) for Hit mice in both tests one and two. However, cognitive performance in T-maze active avoidance, anxiety-related behavior in the elevated plus maze, and Water Maze on group 1 were not affected. Water maze data on group 2 yielded significant results (P<0.05) indicating both groups of Hit mice performed worse on percent time in annulus 40 centimeters, and on path length in trials one and three. Treatment with PRE-084 did not ameliorate any of these deficits. On group 2, Hit + PRE-084 mice performed significantly worse than their counterparts on the rotarod test. The data suggest that there are some chronic deficits for at least 5 weeks after rmTBI, and that sigma-1 activation does not reverse negative effects of rmTBI. Ongoing studies are examining the persistence of these deficits in mice 15 weeks after the final injury, which are relevant to rmTBI related deficits in military personnel that persist up to a year. Water maze data is beginning to persistent deficits due to rmTBI in the long-term.