Medical Neurobiology Commons^™

Mistranslating Trnas Alter The Heat Shock Activation By Hsf1, Rebecca Dib

Undergraduate Student Research Internships Conference

Translation, or the production of protein from an mRNA blueprint, is among the most fundamental processes to life as we know it. tRNAs are essential to accurate translation, as they decode the codons of mRNA and recruit corresponding amino acids. Variant tRNAs with anticodon mutations can decrease translational fidelity by recruiting the incorrect amino acid, an aberrant process known as mistranslation. When proteins are produced with incorrect amino acid sequences, they may misfold. The heat shock response functions to alleviate cellular stress caused by misfolded proteins, either by refolding or targeting misfolded proteins for degradation. Hsf1 acts as a transcriptional …

Visualization And Manual Segmentation Of The Post-Mortem Human Amygdala Subnuclei Using Ultra High Field Magnetic Resonance Imaging, Sara M. Pac

Electronic Thesis and Dissertation Repository

The human amygdala is composed of 13 functionally and anatomically distinct subnuclei. Because most nuclei are difficult to distinguish at the microanatomical level, they are also challenging to discern macroscopically. In low field strength magnetic resonance imaging (MRI) studies, the amygdala can be identified only in its entirety. Higher resolution scans can be acquired by employing ultra-high field strength MRI acquisition techniques. We present a step-by-step guide for the manual segmentation of the amygdala subnuclei at ultra-high field 9.4T MRI. Post-mortem human brain specimen amygdala prosections fit for the 9.4T MRI bore allowed for the collection of high resolution T2-weighted …

Characterizing The Heterogeneity Of Adult-Onset Leukoencephalopathy With Axonal Spheroids: A Digital Spatial Profiling Study, Peter Liu

Undergraduate Student Research Internships Conference

Adult-onset leukoencephalopathy with axonal spheroids (ALAS) is a group of hereditary, progressive, neurodegenerative disorders involving primarily the central nervous system white matter (WM). ALAS is characterized by patchy, asymmetrical myelin loss and axonal destruction in the WM, predominantly involving the frontoparietal regions. However, the asymmetrical and heterogenous involvement of different brain regions remains poorly characterized.

In this study, digital spatial profiling was performed to investigate the region-specific expressions of 60 proteins. Conventional immunohistochemistry methods was used validate intrepretation of probes. Using a high-plex and high-throughput method, we provide evidence of regional heterogeneity in ALAS, particularly involving key markers of microglia …

The Role Of The Tau N-Terminal Phosphatase-Activating Domain And Phosphorylation At Thr175 In The Formation Of Tau Cytoplasmic Inclusions, Matthew A. Hintermayer

Electronic Thesis and Dissertation Repository

Cytoplasmic inclusions and fibrils of the microtubule-associated protein tau (tau protein) are a key neuropathological hallmark in tauopathies, including Alzheimer’s disease, chronic traumatic encephalopathy, and amyotrophic lateral sclerosis with cognitive impairment. Previous research has demonstrated that the phosphorylation of tau protein at Thr¹⁷⁵ is sufficient for the initiation of fibril formation both in vitro and in vivo. Here we use mutated tau protein constructs to demonstrate that phosphorylation at Thr¹⁷⁵ results in the aberrant exposure of an N-terminal phosphatase-activating domain (PAD). The tau PAD interacts with protein phosphatase 1 (PP1) leading to the activation of glycogen synthase …

White Matter Inflammation And Executive Dysfunction: Implications For Alzheimer Disease And Vascular Cognitive Impairment, Alexander Levit

Electronic Thesis and Dissertation Repository

White matter integrity is crucial to healthy executive function, the cognitive domain that enables functional independence. However, in the ageing brain, white matter is highly vulnerable. White matter inflammation increases with age and Alzheimer disease (AD), which disrupts the normal function of white matter. This may contribute to executive dysfunction, but the relationship between white matter inflammation and executive function has not been directly evaluated in ageing nor AD. White matter is also particularly vulnerable to cerebrovascular disease, corresponding with the common presentation of executive dysfunction in vascular cognitive impairment (VCI). Thus, white matter may be an important substrate by …

Milder Alzheimer's Disease Pathology In Heart Failure And Atrial Fibrillation, Luciano A. Sposato, Estefania Ruiz Vargas, Patricia M. Riccio, Jon B. Toledo, John Q. Trojanowski, Walter A. Kukull, Lauren E. Cipriano, Antonia Nucera, Shawn N. Whitehead, Vladimir Hachinski

Anatomy and Cell Biology Publications

Introduction:Heart failure (HF) and atrial fibrillation (AF) have been associated with a higher risk of Alzheimer’s disease (AD). Whether HF and AF are related to AD by enhancing AD neuropathological changes is unknown.

Methods:We applied network analyses and multiple logistic regression models to assess the association between HF and AF with severity of AD neuropathology in patients from the National Alzheimer’s Coordinating Center database with primary neuropathological diagnosis of AD.

Results:We included 1593 patients, of whom 129 had HF and 250 had AF. HF and AF patients were older and had milder AD pathology. In the network …

P03. Role Of Prefrontal Cortical Dopamine Transmission In Post-Traumatic Stress Disorder And Opiate Addiction Vulnerability, Jingjing Li

Western Research Forum

Background

PTSD and opiate addiction share strong co-morbidity and the inability to suppress obtrusive memory recall related to either stressful or rewarding experiences may be an underlying neuropsychological feature triggering PTSD and/or addiction. Our previous research has shown that dopamine (DA) transmission in the prefrontal cortex (PFC) strongly modulates emotional memory formation: activation of the DA D4 receptor (D4R) strongly potentiates the emotional salience of normally non-salient fear memories whereas DA D1 receptor (D1R) activation blocks the behavioural recall of fear memory. Thus, while intra-PFC D4 transmission strongly controls the acquisition of emotional memory, D1 transmission is selectively involved in …

Role Of Cerebrovascular Abnormality In Neurodegenerative Disease And Subcortical Ischemic Disease: Ct Perfusion And Pet Imaging, Jun Yang

Electronic Thesis and Dissertation Repository

Clinical studies indicate that about 30% ~ 50% of patients have cognitive impairment after the first or recurrent stroke. Ischemic injury, particularly subcortical lesions, caused by stroke has been demonstrated to further exacerbate cognitive impairment of Alzheimer’s disease (AD) and vascular dementia. However, the mechanisms whereby cerebrovascular abnormalities contribute to neurodegeneration at early stage of disease and eventually to cognitive decline remain unclear. CT perfusion and positron emission tomography (PET) were used to investigate early mechanisms in a rat comorbid model of cerebral ischemia (CI) and β-amyloid (Aβ, a pathological hallmark of AD) toxicity, and in patients with small subcortical …

Resting State Functional Magnetic Resonance And Diffusion Tensor Imaging Of Hemiplegic Cerebral Palsy Patients Treated With Constraint-Induced Movement Therapy: Predictors And Clinically Correlated Evidence Of Neuroplasticity, Kathryn Y. Manning

Electronic Thesis and Dissertation Repository

Hemiplegic cerebral palsy is characterized by unilateral upper limb impairment and patients often compensate by performing most tasks with their unaffected arm. Constraint-induced movement therapy (CIMT) directly combats this learned non-use by casting the unaffected arm and forcing the patient to repetitively practice skills with the hemiplegic limb. Subjects with hemiplegic cerebral palsy were recruited from Holland Bloorview Kids Rehabilitation Hospital, Thames Valley Children’s Centre and McMaster Children’s Hospital. MRI acquisitions and clinical evaluations were collected at baseline, 1 and 6-months later. The case group participated in a CIMT camp after baseline evaluations and was compared to an untreated control …

Intermittent Hypoxia Alters Metabolic And Cardiovascular Neural Pathways, Jason Michael Moreau

Electronic Thesis and Dissertation Repository

Intermittent hypoxia (IH) is a major pathophysiological manifestation of obstructive sleep apnea (OSA). Previous studies have implicated IH in mediating many pathophysiological outcomes associated with OSA. Only few studies have examined IH-induced alterations to central signaling pathways important in cardiovascular and metabolic phenotypes associated with OSA. This thesis employed a rodent model of IH to examine changes to molecular neural pathways associated with metabolic and cardiovascular pathophysiological outcomes of OSA. Acute IH induces a specific negative body energy balance phenotype. This is concomitant to a reduction in body weight and food intake, with an elevation in food conversion efficiency. Increased …

Characterizing Stomatin-Like Protein 2 And Its Role In Neuron Survival, Lisa A. Foris

Electronic Thesis and Dissertation Repository

Stomatin-like Protein 2 (SLP-2) has been identified as a stress-inducible transcript and has been shown to interact with and stabilize mitochondrial proteins. Since mitochondria are critical for neuronal function, we hypothesized that SLP-2 regulates neuron survival in response to stressful stimuli. A conditional SLP-2 knockout mouse (deletion) and the SN56 cell line (upregulation) were employed to study the role of SLP-2 in mitochondrial dynamics and neuron survival. SLP-2 deficient primary cortical neurons displayed significantly decreased levels of various mitochondrial respiratory chain proteins, indicating SLP-2 contributes to maintenance of mitochondrial membrane integrity. SLP-2 was up-regulated in response to oxidative stress and …

The Role Of Ca2+/Calmodulin Dependent Protein Kinase Ii Alpha In Group 1 Metabotropic Glutamate Receptor Endocytosis And Signalling, Stephanie C. Kulhawy

Electronic Thesis and Dissertation Repository

Group 1 metabotropic glutamate receptors (mGluR1 and mGluR5) are G-protein coupled receptors (GPCRs) activated by glutamate. mGluR1/5 couples to Gα_q/11 and releases Ca²⁺ from the endoplasmic reticulum. Ca²⁺/calmodulin-dependent protein kinase II alpha (CaMKIIα) can be activated by Gα_q/11-mediated Ca²⁺ release through binding of Ca²⁺/calmodulin. Results from a proteomic screen identified CaMKII as a novel mGluR-interacting protein. Therefore, we hypothesized that CaMKIIα associates with group 1 mGluRs and this association alters mGluR1/5 signalling and internalization. Firstly, we demonstrated the novel association between CaMKIIα and mGluR1/5 by co-immunoprecipitation of transiently transfected proteins in …

Trpm2 In The Central Nervous System: Physiological Role And Critical Regulatory Pathways, Jillian C. Belrose

Electronic Thesis and Dissertation Repository

TRPM2 is a non-selective cation channel which is permeable to calcium. Although expression is highest in the brain, the physiological role for TRPM2 in neurons was unknown. Furthermore, our understanding of the pathways regulating TRPM2 channel function required further investigation. In this thesis, we identified that TRPM2 is required for NMDAR-dependent long-term depression (LTD). No change in NMDAR expression or function was observed following genetic deletion of TRPM2. Instead, the loss of NMDAR-LTD in TRPM2 knockout mice results from diminished GSK-3β activation. We next examined whether age in vitro could facilitate TRPM2 currents. We demonstrate that diminished glutathione with age …

Dna Damage And Oxidative Stress Induced-P53 Activity In Astrocytes Causes Growth Arrest, Sarah A. Humphrey

Electronic Thesis and Dissertation Repository

An increasing body of evidence suggests that astrocytes play a key role in modulating neuronal fate during acute and chronic neurodegenerative conditions. Following CNS injury, an upregulation of p53 has been noted in both neurons and reactive astrocytes. p53 is an extremely important protein in determining cell fate decisions and its activation can result in the transcriptional induction of target genes that regulate apoptosis, autophagy, senescence and cell-cycle arrest. We found that p53 is upregulated in primary cortical astrocytes following oxidative stress and DNA damage and that this upregulation results in the p53-dependent transcriptional induction of several target genes involved …