Neuroscience and Neurobiology Commons^™

The Effects Of Physical Function And Genetics On Cognition And Blood Biomarkers In Individuals At-Risk For Alzheimer’S Disease And Related Dementias, Joshua Louis Gills

Graduate Theses and Dissertations

Alzheimer’s disease and related dementia (ADRD) rates are expected to triple by the year 2050. Early detection and specific mitigation efforts are warranted to blunt the alarming rate. Physical function (PF) declines with age, but higher physical function is associated with better cognitive functioning in middle-to- older age individuals. Moreover, greater physical activity (PA) is associated with better global cognition; however, Apoliporotein e4 carriers may not gain the same benefits with exercise. Additionally, plasma phosphorylated tau 217 (p-tau217) has been identified as a novel diagnostic ADRD biomarker which needs further research to examine associations with risk factors. Therefore, the aims …

Mirnas Levels In A Streptozocin Model Of Alzheimer’S Disease, Nada Moustafa

Theses and Dissertations

Dementia entails a progressive decrease in cognitive functions, with 50%-75% of cases attributed to Alzheimer’s disease (AD); an aging-associated condition characterized by the build-up of tangled phosphorylated Tau (p-Tau) protein and beta-amyloid (Aβ) depositions. Sporadic AD (sAD) is multifactorial in nature, resulting from a combination of environmental and genetic predisposing factors. Type 2 diabetes mellitus (T2DM) is a leading risk factor for dementia, and deregulation of brain glucose metabolism is associated with early cognitive affection in sAD. Thus, the diabetogenic agent Streptozotocin (STZ) is used to experimentally create an AD model in animals (STZ-induced sAD), in which abnormalities in cerebral …

Alzheimer's And Patient Caregiver Burnout: A Review Of The Literature, Madeline Hekeler

James Madison Undergraduate Research Journal (JMURJ)

The term “silent epidemic” is fitting for Alzheimer’s disease (AD), as its negative impact is widely felt but rarely discussed. Burnout among AD caregivers has become an epidemic of its own as caregivers experience an increase in health risks, stress, and financial burden. This literature review focuses on caregiver burnout and how imperative it is that caregivers are better supported in their role. Researchers have developed instruments to assess and intervene in caregiver burnout that have shown effectiveness among caregivers and their families.Nevertheless, further longitudinal research is warranted regarding more effective interventions, including stress management and social support mechanisms.

Therapeutic Treatment With The Anti-Inflammatory Drug Candidate Mw151 May Partially Reduce Memory Impairment And Normalizes Hippocampal Metabolic Markers In A Mouse Model Of Comorbid Amyloid And Vascular Pathology, David J. Braun, David K. Powell, Christopher J. Mclouth, Saktimayee M. Roy, D. Martin Watterson, Linda J. Van Eldik

Neuroscience Faculty Publications

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, but therapeutic options are lacking. Despite long being able to effectively treat the ill-effects of pathology present in various rodent models of AD, translation of these strategies to the clinic has so far been disappointing. One potential contributor to this situation is the fact that the vast majority of AD patients have other dementia-contributing comorbid pathologies, the most common of which are vascular in nature. This situation is modeled relatively infrequently in basic AD research, and almost never in preclinical studies. As part of our efforts to develop …

Potential And Limitations Of Using Stem Cells To Cure Alzheimer’S Disease: A Literature Review Of Its Potential And Ethical Limitations In Translation To Human Trials, Eleni Zivla

OUR Journal: ODU Undergraduate Research Journal

Alzheimer's disease has become one of the most significant, life-limiting illnesses of our time as a result of the rapid increase in the average life expectancy. To successfully develop a cure for this yet incurable disease, one must understand the pathology of Alzheimer’s disease. As found in recent research studies, a brain that is diagnosed with Alzheimer's is characterized by the presence of extracellular amyloid plaques composed of the amyloid-beta (Aβ) peptide and intracellular neurofibrillary tangles composed of the microtubule-associated protein: tau. In this literature review, several stem cell therapies are being reviewed as a potential cure for Alzheimer’s disease …

Ab42 Alters Glutamatergic Transmission In The Ca1 Region Of The Mouse Hippocampus, Patrick Harry Wehrle

Legacy Theses & Dissertations (2009 - 2024)

Alzheimer’s disease (AD) is a neurodegenerative disease affecting 4.5 million people in the US, a number expected to increase 3-fold over the next 30 years. One of the hallmarks of AD is the extracellular accumulation of the protein Aß₄₂ throughout in the brain, particularly in limbic structures like the temporal cortex and hippocampus, key regions for learning and memory. Currently available animal models for AD aim to reproduce key genetic traits of the familial variant of the disease, but >90% of AD patients are affected by idiopathic AD. To overcome this potential limitation, we use a different approach to study …

Editorial: Roles Of Sleep Disruption And Circadian Rhythm Alterations On Neurodegeneration And Alzheimer's Disease, Marilyn J. Duncan, Sigrid C. Veasey, Phyllis Zee

Neuroscience Faculty Publications

No abstract provided.

Validation Of Induced Microglia-Like Cells (Img Cells) For Future Studies Of Brain Diseases, Atoshi Banerjee, Yimei Lu, Kenny Do, Travis Mize, Xiaogang Wu, Xiangning Chen, Jingchun Chen

School of Medicine Faculty Publications

Microglia are the primary resident immune cells of the central nervous system that maintain physiological homeostasis in the brain and contribute to the pathogenesis of many psychiatric disorders and neurodegenerative diseases. Due to the lack of appropriate human cellular models, it is difficult to study the basic pathophysiological processes linking microglia to brain diseases. In this study, we adopted a microglia-like cellular model derived from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-34 (IL-34). We characterized and validated this in vitro cellular model by morphology, immunocytochemistry, gene expression profiles, and functional study. Our results indicated that the iMG …

Intepirdine As Adjunctive Therapy To Donepezil For Mild-To-Moderate Alzheimer’S Disease: A Randomized, Placebo-Controlled, Phase 3 Clinical Trial (Mindset), Frederick M. Lang, Yi Mo, Marwan Sabbagh, Paul Solomon, Merce Boada, Roy W. Jones, Giovanni B. Frisoni, Timo Grimmer, Bruno Dubois, Mark Harnett, Sarah R. Friedhoff, Shari Coslett, Jeffrey L. Cummings

Brain Health Faculty Publications

Introduction: A previous phase 2b study supported the use of the 5-HT6 receptor antagonist intepirdine as adjunctive therapy to donepezil for Alzheimer's disease (AD) dementia. A phase 3 study, MINDSET, was performed to test this hypothesis. Methods: MINDSET was a global, double-blind, randomized, placebo-controlled trial in 1315 mild-to-moderate AD dementia patients on stable donepezil. Patients received 35 mg/day intepirdine or placebo for 24 weeks. The co-primary endpoints were change from baseline to week 24 on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). Results: There were no statistically significant differences between intepirdine …

Repeated Electromagnetic Field Stimulation Lowers Amyloid-Β Peptide Levels In Primary Human Mixed Brain Tissue Cultures, Nipun Chopra, Felipe P. Perez, Bryan Maloney, Jorge J. Morisaki, Debomoy K. Lahiri

Biology Faculty publications

Late Onset Alzheimer’s Disease is the most common cause of dementia, characterized by extracellular deposition of plaques primarily of amyloid-β (Aβ) peptide and tangles primarily of hyperphosphorylated tau protein. We present data to suggest a noninvasive strategy to decrease potentially toxic Aβ levels, using repeated electromagnetic field stimulation (REMFS) in primary human brain (PHB) cultures. We examined effects of REMFS on Aβ levels (Aβ40 and Aβ42, that are 40 or 42 amino acid residues in length, respectively) in PHB cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro 7 (DIV7) treated with 64 …

Comparison Of Longitudinal Changes In Resting State Functional Magnetic Resonance Imaging Between Alzheimer’S And Healthy Controls, Berk Can Yilmaz

Theses

Resting State Functional Magnetic Resonance Imaging (rs-fMRI) is a technique that is widely used for analyzing brain function using different approaches and methods. This study involves rs-fMRI analysis of Blood Oxygenation Level Dependent (BOLD) signals acquired from Alzheimer’s disease (AD) Patients and Healthy Controls (HC). Each subject in the study had both functional and anatomical images with at least one rs-fMRI scan with their Anatomical (T1) scans. Previous rs-fMRI studies have demonstrated that AD shows differences in Amplitude of Low Frequency (<0.1 Hz) Fluctuations (ALFF), and Regional Homogeneity (ReHo) measures according to HCs.

The aim of the study is to investigate individual and group level differences using ReHo and mALFF related …

Nutraceutical Potential For Alzheimer's Disease Treatment, Alex Gewecke

Undergraduate Research Journal

Alzheimer’s disease (AD) is a progressive disorder involving buildup of excessive amounts of proteins such as beta amyloid in the brain that leads to memory loss, inability to perform daily functions, and an early death. By 2060, the number of cases is forecast to nearly triple current numbers. Age is the primary risk factor for AD and no new drugs have been approved since 2003. Nutraceuticals, a broad category of substances that can be utilized for both medicinal and nutritional purposes may be able to help, which is why they are being more widely researched. Overall, a number of attempts …

Investigation Of The Role Of Heparin-Binding Pocket In Amyloid Fibrils Formation Of Fgf-1, I Gusti Ayu Agung Septiari

Graduate Theses and Dissertations

Human acidic fibroblast growth factor (aFGF/hFGF-1) is one of the promising molecules to be investigated to generate an in-depth understanding of the pathological mechanism of Alzheimer's disease (AD) neurodegenerative disorder characterized by the presence of amyloid fibrils. Some in vivo and human brain tissue studies proved the correlation of high-level expression of FGF-1-induced neuroinflammation and the occurrence of AD. The presence of amyloid fibrils as a hallmark of AD can be related to the generic property of the proteins to form amyloid fibrils; High level of FGF-1, in this case, may contribute to the formation of amyloid fibrils. As a …

Cytotoxic Analysis Of Old Drugs: New Drugs For Alzheimer’S Disease, Sebastian Yumiseba

Theses and Dissertations

Microglia are the resident immune cells of the CNS and constitute about 10% of all cells in the CNS. They have a vital role in Alzheimer’s pathogenesis as either cytotoxic or neuroprotective. Recent efforts are being put into repurposing drugs to target the microglia to treat Alzheimer’s disease.

Regulation And Function Of Trem2-Dependent Pathways In Neurodegeneration, Wilbur Madison Song

Arts & Sciences Electronic Theses and Dissertations

Carriers of the R47H allele of the microglia-specific lipid receptor TREM2 have a greatly increased risk of developing Alzheimerճ disease. The objective of this dissertation is to develop further mechanistic knowledge about how TREM2 is regulated and how TREM2 mutations affect microglia and neurodegeneration. Using an in vitro reporter assay, we find that several AD risk-associated TREM2 mutations decrease ligand-dependent activation. Using humanized TREM2 mice, we find that in vivo, the R47H mutation leads to reduced microglia activation and response to A_, as well as decreased shedding of soluble TREM2. These results suggest that TREM2 is protective during disease. We …

A Study Of The Antioxidant Versus Pro-Oxidant Nature Of The Amyloid Beta Peptide And An Analysis Of The Natural Products, Isorhamnetin And Narignenin, As Antioxidants, Kaylee Holmes

Honors Theses

Alzheimer’s disease is a neurodegenerative disorder with no cure. Due to the widespread effects of this disease, abundant research efforts have gone towards finding a cure. The amyloid beta (Ab) peptide has been shown to be a potential cause of the disease due to destructive effects on tissues that it can have both by itself and through reactive oxygen species (ROS) generation. This study was performed in order to assess the structural properties of Ab₄₂monomers, fibrils and oligomers, to assess the antioxidant versus pro-oxidant behavior of the Ab peptide, and to assess the antioxidant nature of the natural …

Divergence In Neuronal Calcium Dysregulation In Brain Aging And Animal Models Of Ad, Adam Ghoweri

Theses and Dissertations--Pharmacology and Nutritional Sciences

Neuronal calcium dysregulation first garnered attention during the mid-1980’s as a key factor in brain aging, which led to the formulation of the Ca²⁺ hypothesis of brain aging and dementia. Indeed, many Ca²⁺-dependent cellular processes that change with age, including an increase in the afterhyperpolarization, a decrease in long-term potentiation, an increased susceptibility to long-term depression, and a reduction in short-term synaptic plasticity, have been identified. It was later determined that increased intracellular Ca²⁺ with age was due to increased Ca²⁺ channel density, elevated release from intracellular Ca²⁺ stores, and decreased Ca²⁺ buffering …

Alzheimer's Disease Drug Development Pipeline: 2020, Jeffrey Cummings, Garam Lee, Aaron Ritter, Marwan Sabbagh, Kate Zhong

School of Medicine Faculty Publications

© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association. Introduction: Alzheimer's disease (AD) is a growing public health concern affecting millions of patients worldwide and costing billions of dollars annually. We review the pipeline of drugs and biologics in clinical trials for the treatment of AD. We use the Common Alzheimer's and Related Dementias Research Ontology (CADRO) to classify treatment targets and mechanisms of action. We review our annual pipeline reports for the past 5 years to provide longitudinal insight into clinical trials and drug development for …

Executive Function Deficit As A Precursor To Memory Impairments In Hapoe4 Transgenic Rats, Kaitlin Mcmanus

Honors Theses

The hApoE4 allele is one of the strongest genetic risk factors for Alzheimer’s disease (AD). It underlies amyloid-bdeposits and neurofibrillary tangles, the two hallmarks associated with AD pathology, and is subsequently associated with AD symptomology. Despite its importance, no rat animal studies to date use hApoE4 knock-ins. In addition to this deficit in the field of AD literature, the vast majority of AD studies focus on memory, even though executive function deficits may precede memory impairments in AD, and may be a predictor of AD development. Thus, the present study addressed these gaps in AD research by investigating the behavioral …

The Effect Of Traumatic Brain Injury On Tau Pathology By A Potential Seeding Mechanism, George Edwards Iii

Dissertations & Theses (Open Access)

The misfolding, aggregation and accumulation of specific proteins is the overarching concept in protein misfolding disorders (PMDs). The microtubule associated protein tau is known to form insoluble filaments known as neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (pTau) found in a subset of PMDs called tauopathies, such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE), among others. Misfolded tau engenders a structurally alternative intermediate conformation that is prone to aggregate having amyloidogenic properties. Formation of amyloids, such as tau aggregates, is proposed to follow a nucleation-polymerization model where misfolded, soluble oligomeric seeds can trigger native proteins to misfold and …

Lysosomes Mediate Rab27b-Dependent Secretion Of Beta-Amyloid, Shany Lahan

Electronic Thesis and Dissertation Repository

Extracellular deposition of beta-Amyloid (Aβ) is an early event in Alzheimer’s disease development. However, it is not known how Aβ is secreted. Lysosomes readily undergo calcium-dependent exocytosis, a process that relies on small GTPase Rab27b. In addition, lysosomal enzymes have been found within extracellular amyloid plaques. We hypothesized that lysosomes mediate Rab27b-dependent exocytosis of Aβ. Neuro-2a cells were transfected with wild-type or mutant Rab27b constructs and/or a lysosomal marker. Cells were incubated with Aβ monomers and imaged using a confocal microscope before and after stimulation of calcium-dependent exocytosis. We observed a significant decrease in lysosome and Aβ co-localization post-treatment in …

Integrative Analysis To Investigate Complex Interaction In Alzheimer’S Disease, Zeran Li

Arts & Sciences Electronic Theses and Dissertations

Alzheimer’s disease (AD) is a neurodegenerative disorder featuring progressive cognitive and functional deficits. Pathologically, AD is characterized by tau and amyloid β protein deposition in the brain. As the sixth leading cause of death in the U.S., the disease course usually last from 7 to 10 years on average before the consequential death. In 2019 there are estimated 5.8 million Americans living with AD affecting 16 million family members. At certain stage of the disease course, patients with inability of maintaining their daily functioning highly depend on caregivers, primarily family caregivers, that incur estimated 18.4 billion unpaid hours of cares, …

Memory-Based Viewing: A Potential Marker Of Pathological Aging, Jenna Blujus

Theses and Dissertations

Markers of cognitive impairment are needed to distinguish normal from pathological aging prior to the onset of clinical symptomology to improve Alzheimer’s disease (AD) treatment or prevention efforts. AD pathology is believed to develop years or even decades prior to diagnosis in medial temporal lobe subregions that provide input to the hippocampus (Braak & Braak, 1991), disrupting the ability of the hippocampus to bind individual elements of an experience to form cohesive memory representations. Eye movement behavior is a sensitive index of learning and effects of memory on eye movements have been shown to emerge rapidly (within 500-750ms of stimuli …

Memory-Based Viewing: A Potential Marker Of Pathological Aging, Jenna Blujus

Theses and Dissertations

Markers of cognitive impairment are needed to distinguish normal from pathological aging prior to the onset of clinical symptomology to improve Alzheimer’s disease (AD) treatment or prevention efforts. AD pathology is believed to develop years or even decades prior to diagnosis in medial temporal lobe subregions that provide input to the hippocampus (Braak & Braak, 1991), disrupting the ability of the hippocampus to bind individual elements of an experience to form cohesive memory representations. Eye movement behavior is a sensitive index of learning and effects of memory on eye movements have been shown to emerge rapidly (within 500-750ms of stimuli …

Validity And Reliability Of A 5-Minute Web-Camera Based Eye Tracking Test To Assess Visual Memory And Cognition, Emily Bates

Graduate Theses and Dissertations

There are approximately 5.7 million Americans currently living with Alzheimer’s Disease (AD). Early detection of cognitive impairment allows for earlier treatment, potentially slowing or halting cognitive decline. A 30-min web-camera eye tracking assessment (30-min VPC) has been validated as a tool to predict AD risk. However, a shorter version would allow for greater scalability and improve user experience. The purpose of this study was to: 1) determine the validity of the 5-minute web-camera based VPC test with the 30-min test, 2) determine the test-retest reliability of the 5-min test, 3) compare the 5-minute test scores of cognitively intact adults (18-39 …

Cerebrovascular Smooth Muscle Cells As The Drivers Of Intramural Periarterial Drainage Of The Brain, Roxana Aldea, Roy O. Weller, Donna M. Wilcock, Roxana O Carare, Giles Richardson

Physiology Faculty Publications

The human brain is the organ with the highest metabolic activity but it lacks a traditional lymphatic system responsible for clearing waste products. We have demonstrated that the basement membranes of cerebral capillaries and arteries represent the lymphatic pathways of the brain along which intramural periarterial drainage (IPAD) of soluble metabolites occurs. Failure of IPAD could explain the vascular deposition of the amyloid-beta protein as cerebral amyloid angiopathy (CAA), which is a key pathological feature of Alzheimer's disease. The underlying mechanisms of IPAD, including its motive force, have not been clarified, delaying successful therapies for CAA. Although arterial pulsations from …

The Characterization Of Alzheimer’S Disease And The Development Of Early Detection Paradigms: Insights From Nosology, Biomarkers And Machine Learning, Isabel Milano

CMC Senior Theses

Alzheimer’s Disease (AD) is the only condition in the top ten leading causes of death for which we do not have an effective treatment that prevents, slows, or stops its progression. Our ability to design useful interventions relies on (a) increasing our understanding of the pathological process of AD and (b) improving our ability for its early detection. These goals are impeded by our current reliance on the clinical symptoms of AD for its diagnosis. This characterizations of AD often falsely assumes a unified, underlying AD-specific pathology for similar presentations of dementia that leads to inconsistent diagnoses. It also hinges …

Investigating Neurogenesis As A Veritable Epigenetic Endophenotype For Alzheimer's Disease, Layne Wells

Scripps Senior Theses

Alzheimer's disease (AD) is the most common neurodegenerative disease, characterized by progressive amyloid plaque aggregation, neurofibrillary tangles, and cortical tissue death. As the prevalence of AD is projected to climb in coming years, there is a vested interest in identifying endophenotypes by which to improve diagnostics and direct clinical interventions. The risk for complex disorders, such as AD, is influenced by multiple genetic, environmental, and lifestyle factors. Significant strides have been made in identifying genetic variants linked to AD through the genome-wide association study (GWAS). It has been estimated in more recent years, however, that GWAS-identified variants account for limited …

Effects Of The Dual Orexin Receptor Antagonist Dora-22 On Sleep In 5xfad Mice, Marilyn J. Duncan, Hannah Farlow, Chairtra Tirumalaraju, Do-Hyun Yun, Chanung Wang, James A. Howard, Madison N. Sanden, Bruce F. O'Hara, Kristen J. Mcquerry, Adam D. Bachstetter

Neuroscience Faculty Publications

Introduction: Sleep disruption is a characteristic of Alzheimer's disease (AD) that may exacerbate disease progression. This study tested whether a dual orexin receptor antagonist (DORA) would enhance sleep and attenuate neuropathology, neuroinflammation, and cognitive deficits in an AD-relevant mouse model, 5XFAD.

Methods: Wild-type (C57Bl6/SJL) and 5XFAD mice received chronic treatment with vehicle or DORA-22. Piezoelectric recordings monitored sleep and spatial memory was assessed via spontaneous Y-maze alternations. Aβ plaques, Aβ levels, and neuroinflammatory markers were measured by immunohistochemistry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction, respectively.

Results: In 5XFAD mice, DORA-22 significantly increased light-phase sleep without reducing Aβ levels, …

The Role Of Apolipoprotein E In Regulating Tau Pathogenesis And Neurodegeneration In A Tauopathy Mouse Model, Yang Shi

Arts & Sciences Electronic Theses and Dissertations

APOE4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). APOE4 increases brain amyloid-β (Aβ) pathology relative to other APOE isoforms. However, whether APOE independently influences tau pathology, the other pathological hallmark of AD and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human APOE knock in (KI) or APOE knockout (KO) background, we show that the presence of human APOE, regardless of APOE isoforms, leads to various degrees of brain atrophy in 9-month old P301S mice, whereas APOE ablation strongly protects against neurodegeneration. In particular, P301S/E4 mice develop …