Browsing by Subject "neurodegeneration"
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Item Alpha synuclein functions as a sex-specific modulator of cognition and gene expression(2022-12) Brown, JenniferNeurodegenerative diseases such as Alzheimer’s and Parkinson’s impact large portions of the population. Though such diseases have distinguishing features, they also often share pathology and symptomology. Alpha synuclein (αSyn; gene SNCA) is a protein commonly found in a range of neurodegenerative conditions. αSyn can interact with tau and amyloid-beta to modulate disease phenotypes, but its normal functions remain incompletely characterized. To explore the contribution of αSyn to Alzheimer’s disease, I first asked whether reducing αSyn in a mouse model of Alzheimer’s would improve cognition. Using a translationally relevant strategy, the reduction of αSyn reveled a sex-specific effect whereby male, but not female, mice showed improved spatial memory. Follow-up studies with constitutive SNCA knockout mice revealed a previously unreported female-specific deficit in spatial learning and memory. Next, we utilized electrophysiology, immunofluorescence imaging and transcriptomics to elucidate potential mechanisms underlying this effect. Results revealed a novel impairment in long-term potentiation, as well as differential expression of genes related to learning and immune function in female mice in response to SNCA ablation. These results not only describe a novel sex-specific function of αSyn, but provide translationally-relevant information regarding the potential effects of using αSyn reduction as a therapeutic strategy for neurodegenerative conditions.Item Cellular And Molecular Mechanism Of Action Of The Amyloid-Beta Oligomer Abeta Star 56(2016-01) Amar, FatouAlzheimer’s disease (AD) is a progressive neurodegenerative disorder, with asymptomatic and symptomatic phases. Hallmark lesions of AD include extracellular deposits of fibrillar amyloid-β (A β) and intracellular Neurofibrillary tangle formations (NFTs). However, recent evidence seems to support soluble oligomeric forms of amyloid proteins as bioactive species in AD. Amyloid-β oligomers (Aβo), such as Aβ*56, Aβ dimers and trimers have been demonstrated to be synaptotoxic species in AD. In particular, one of these oligomers, Aβ*56, was found to cause cognitive decline in the AD mouse model Tg2576, despite the absence of plaques and neuronal loss. In addition, cross-sectional studies suggest its possible involvement in the asymptomatic or preclinical phase of AD. However, it is currently unclear how this specific oligomer (Aβ*56) influences cellular and molecular processes to lead to cognitive deficits. My thesis focused on how Aβ*56 is able to disrupt cognition at the cellular and molecular level. First, we demonstrate that Aβ*56 forms a complex with NMDA receptors (NMDARs) resulting in an aberrant increase in intracellular calcium driven by synaptic NMDARs and the specific activation of the Ca2+/calmodulin dependent protein kinase CaMKIIα. Active CaMKIIα induces selective pathological changes in tau in vivo and in vitro, involving hyperphosphorylation and missorting. Importantly, other forms of endogenous Aβ oligomers do not appear to trigger these effects. Furthermore, other kinases such as GSK3, Cdk5 and fyn are not modulated by Aβ*56 in vitro. Interestingly, CaMKII phosphorylation is elevated in brain tissue of aged individuals, correlating with Aβ*56 abundance. These findings indicate that distinct Aβ oligomers activate specific neuronal signaling pathways in a highly selective manner in vitro. By extrapolation, these observations may have important consequences relative to our understanding of the different stages of AD.Item Investigation of Monoaminergic Neurotransmitter Systems as a Method to Study Alzheimer's Disease-Related Neurodegeneration(2018-08) Gallardo, ChristopherAlzheimer’s disease (AD) is the most common neurodegenerative disease and leading cause of dementia currently afflicting 5.4 million people in the United States. Memory impairment and cognitive dysfunction are the most recognized clinical manifestations of AD, however, disturbances in vision, sleep, olfaction, psychosis, and depression also impair the normal daily functions of AD patients. These symptoms can be attributed to the defining histopathological changes in AD and loss of neuronal populations in the hippocampus, cortex, olfactory bulb, brainstem, and retina – regions that are responsible for learning, memory, cognition, olfaction, wakefulness, affect, and vision. Current treatments for AD include reversible acetylcholinesterase inhibitors and N-methyl-D¬-aspartate (NMDA) receptor antagonists, however, these medications only provide mild symptomatic benefits in a subset of AD patients. A great deal of work aimed at understanding the ongoing pathological processes in AD and its progression have resulted in a wealth of transgenic mouse models currently saturating the field. However, despite the abundance of AD mouse models available, most of these models have failed to recapitulate substantial neuronal loss in regions relevant to AD [1-4]. Specifically, mouse models of Aβ pathology fail to show subsequent NFT/NT formation and profound neurodegeneration. In contrast, models of tauopathy vary in their neurodegenerative phenotype, but typically rely on mutant tau transgenes that are not seen in AD [1, 5]. Taken together, these findings have led to the notion that Aβ/APP models of AD only recapitulate the earliest changes of the disease and are alone insufficient to cause progressive neurodegeneration [6]. To address whether Aβ pathology is indeed sufficient for progressive neurodegeneration, recent work looked at neuronal populations in the brainstem where the dorsal raphe (DR) and locus coeruleus (LC) degenerate early in AD [7-11]. These DR and LC regions contain serotonergic and noradrenergic neurons, respectively, which send out abundant projections throughout the entire brain [10, 12-16]. Early work on human AD samples showed that the DR and LC neurons are among the earliest affected in the disease process [9-11, 17-20]. Interestingly, this degeneration is limited to the anteromedial portions of the DR and LC, while caudal regions are left unaffected. This topography of tau pathology and neurodegeneration is consistent with the fact that rostro-medial portions send their axonal projections to cortical and hippocampal regions, which display abundant amyloid pathology. The caudal DR and LC, however, send their projections to the spinal cord and cerebellum – areas without amyloid deposition – and are, thus, spared from neurodegenerative changes [10, 21, 22]. Findings in the APPSwe/PS1ΔE9 line showed that progressive axonal and somatic degeneration of serotonin and noradrenergic neurons followed persistent Aβ deposition/pathology [7]. Furthermore, this degeneration could be attenuated with the administration of anti-Aβ immunotherapy [8]. The analyses of brainstem monoaminergic (MAergic) systems in the APPSwe/PS1ΔE9 was the first to show that Aβ pathology could induce progressive neurodegeneration in vivo [23]. Subsequent studies expanded on these observations showing degeneration initiating at axon terminals and progressing to cell body degeneration [7]. Furthermore, defining a potential cellular or molecular mechanism for MAergic neurodegeneration remains unanswered. To better identify the factors leading to MAergic neurodegeneration in mouse models of Aβ pathology, we set out to address certain questions that were left open. First, is degeneration of MAerigc systems a common feature of Aβ mouse models? Second, is MAergic degeneration dependent on an interaction between mutant APP and PS1 transgenes? Third, is degeneration of MAergic systems dependent on Aβ signaling through cellular prion protein (PrPC)? By utilizing a mouse model expressing mutant APP transgenes in the absence of mutant PS1, known as the J20 model, we show that MAergic degeneration is also recapitulated in this mouse model (chapter 2). The presence of MAergic degeneration in this model, in addition to other previously observed models, supports the argument that Aβ pathology is sufficient for MAergic neurodegeneration. Furthermore, the absence of a mutant PS1 transgene in the J20 model indicates that MAergic neurodegeneration is indeed due to Aβ toxicity, not an artificial interaction between mutant APP and PS1 transgenes. Interestingly, by comparing the results from the J20 model to the previously reported APPSwe/PS1ΔE9 model, we observe differential onsets on Aβ deposition and MAergic neurodegeneration. Specifically, the J20 model has an approximate 3-4 month delay in Aβ pathology compared to the APPSwe/PS1ΔE9 mouse model. This results in a delay in the onset of MAergic degeneration. Whereas axonal degeneration begins at 8 months in the APPSwe/PS1ΔE9 model [7], when Aβ deposits are abundant, J20 mice just begin to show Aβ plaques at this time point and MAergic axons are still intact. Looking at aged mice (~16 months), J20 mice have significantly less noradrenergic axonal afferents in cortical and hippocampal regions, but no loss of MAergic cell bodies. In contrast, APPSwe/PS1ΔE9 animals at this age show a significant loss of MAergic neurons consistent with the earlier onset of MAergic axonal degeneration (Table 1.1.) [7]. To address whether PrPC is essential for MAergic neurodegeneration, we utilized a genetic approach to conditionally remove the Prnp gene, which encodes PrPC. Recent work by several labs have shown that PrPC is essential in Aβ toxicity. Specifically, constitutive removal of the Prnp gene, which encodes PrPC, fully rescues spatial learning and memory impairments in APPSwe/PS1ΔE9 mice [24]. However, given that the current diagnosis of AD occurs after Aβ deposition has already occurred, understanding whether conditional deletion of Prnp may provide a better understanding to the potential efficacy of targeting PrPC in patients. By using a Cre-Lox system to conditionally remove PrPC in APPSwe/PS1ΔE9, we are able to address if inhibiting Aβ oligomer (Aβo) signaling through PrPC is able to attenuate ongoing MAergic neurodegeneration (chapter 3). Despite efforts to identify mediators of Aβ toxicity in AD, the mechanistic insight triggering neurodegeneration remains poorly understood. Some of this ambiguity may be due to the inability of preclinical mouse models to capture the complexity of human AD cases. However, by looking at other systems affected in AD, it may be possible to better understand the cellular events leading to neurodegeneration. The classical view of AD is that it is memory disorder, but multiple faculties become compromised in people affected by the disease. Vision impairment has been noted as an early symptom in AD cases and has remained an interesting topic of investigation [25]. The association between vision and cognition or specifically, age-related macular degeneration (AMD) and AD have been explored several times in the past 25 years [25-37]. While AMD and AD, or vision and cognition, may seem as an unlikely link, multiple studies have confirmed the ability of poor vision to negatively impact cognition [25, 34-36]. Population based studies following individuals with early and late AMD have shown increased incidences of cognitive impairment compared to controls without AMD [26-28, 35]. Cognitive impairment, on the other hand, does not seem to affect vision [32]. Thus, the current interpretation is that vision impairment occurs early in AD and may represent a possible mode of detecting early AD and predicting disease severity. Still, conclusions about AMD and AD are controversial. Possible causes of this controversy may include the different methods of testing for visual and cognitive functions as well as how to properly control for risk factors. Indeed, Baker and colleagues (2009) found that early AMD was associated with lower cognitive tests. When they evaluated their results again using a modified mini mental state exam (mMMSE), this association was no longer present. Another study found associations between AMD and risk of AD, but not after controlling for smoking and atherosclerosis [26]. By evaluating common pathologies in AMD and AD, it may be possible to understand the potential mechanisms leading to cell loss. Using the links between AMD and AD, (such as risk factors, inflammation, and oxidative stress) we set out to establish a method to investigate cell loss in AMD and AD. Specifically, inflammation, oxidative stress, and mitochondrial DNA (mtDNA) damage are seen in degenerating regions of the eye in AMD and degenerating regions of the brain in AD [38-44]. By looking at human control and AMD tissues, we show that mtDNA damage is present in AMD retinal pigment epithelium (RPE) cells (chapter 4). However, mtDNA damage is not increased in the neural retina [41, 44]. Following up on these results, we show that at a stage characterized as “dry” AMD, there is no relationship RPE and retinal mtDNA damage in individual donors [41]. This demonstrated that mtDNA damage as an important change leading to cell death. By using the long-extension PCR (LX-PCR) technique to evaluate mtDNA damage for AMD, this technique may also be used to evaluate degenerating DR and LC neurons in AD.Item Methamphetamine, Neurodegeneration, and Differential Vulnerability of Dopamine Neurons(2021-07) Lee, You BinMethamphetamine (meth) is an addictive and neurotoxic psychostimulant. Meth increases monoamine oxidase (MAO)-dependent axonal mitochondrial stress in substantia nigra pars compacta (SNc) dopamine (DA) neurons and chronic meth administration causes MAO-dependent SNc degeneration. Ventral tegmental area (VTA) neurons also express and utilize MAO to metabolize DA. The current study examined whether VTA neurons are vulnerable or resistant to chronic meth-induced degeneration and underlying mechanisms. We found that, similar to findings in SNc axons, meth induced MAO-dependent mitochondrial stress in VTA axons; however, the VTA was resistant to chronic meth-induced degeneration. The differentiating feature between SNc and VTA neurons was that SNc axons also had L-type Ca2+ channel (LCC)-dependent mitochondrial stress whereas VTA neurons did not. Both MAO and LCC inhibition attenuated meth-induced degeneration of SNc neurons as did a mitochondrial antioxidant. Together these data suggest that both MAO- and LCC-dependent mitochondrial stress are necessary for meth-induced degeneration.Item Pharmacology and Clinical Effects of N-acetylcysteine in Neurodegenerative Disorders(2015-08) Holmay, MaryFree radicals and other reactive oxygen species (ROS) constitute a normal part of the intracellular environment. Endogenous enzymes such as catalase, superoxide dismutase and the thiol redox systems, glutathione and oxidized glutathione, serve as reducing agents to minimize the harm ROS might cause in the cell. An excess of ROS, however, can tilt the delicate balance leading to oxidative stress. It is now well known that oxidative stress (OS) plays an important role in many neurodegenerative disorders such as Parkinson disease, Alzheimer’s disease, amyotrophic lateral sclerosis and other disorders with neurodegenerative effects, including adrenoleukodystrophy (ALD). Many antioxidants have been studied in an effort to ameliorate the oxidative stress, slow the progression or treat the symptoms of these and other neurodegenerative disorders, mostly with limited success. The potential reasons for the limited success of these compounds are discussed in this thesis, and the dissertation research on the potential use of N-acetylcysteine, (NAC) a well-known antioxidant and glutathione precursor, is described in detail. The first portion of the dissertation research described herein focused on characterizing the pharmacokinetics of intravenously administered NAC as adjunctive therapy with hematopoietic cell transplant (HCT) in ALD. The objectives of this research were to characterize the pharmacokinetics of i.v. NAC and to explore one of the mechanisms by which NAC is thought to exert its antioxidant effects: through the provision of cysteine for the synthesis of glutathione, the most powerful endogenous antioxidant in the body. The second clinical study described in this thesis focused on the effect of i.v. administered NAC on glutathione concentrations measured directly in the brain of people with Parkinson’s disease, Gaucher disease and healthy control subjects, through the use of magnetic resonance spectroscopy. The research described in this dissertation represents the first report of the pharmacokinetics and direct pharmacodynamic effects of i.v. NAC administration in those affected by disorders of neurodegeneration. This research now serves as the basis for other pharmacokinetic and pharmacodynamic studies of NAC in other populations as well as with other dosage forms and formulations, with the hope of developing effective antioxidant treatments for those suffering from neurodegenerative disorders.