Neurosciences Commons^™

Role Of Membrane Gm1 On Early Neuronal Membrane Actions Of Aβ During Onset Of Alzheimer's Disease, E. J. Fernandez-Perez, Fernando Sepulveda, Robert W. Peoples, Luis G. Aguayo

Biomedical Sciences Faculty Research and Publications

The ability of beta-amyloid peptide (Aβ) to disrupt the plasma membrane through formation of pores and membrane breakage has been previously described. However, the molecular determinants for these effects are largely unknown. In this study, we examined if the association and subsequent membrane perforation induced by Aβ was dependent on GM1levels. Pretreatment of hippocampal neurons with D-PDMP decreased GM1 and Aβ clustering at the membrane (Aβ fluorescent-punctas/20 μm, control = 16.2 ± 1.1 vs. D-PDMP = 6.4 ± 0.4, p < 0.001). Interestingly, membrane perforation with Aβ occurred with a slower time course when the GM1 content was diminished (time to establish perforated configuration (TEPC) (min): control = 7.8 ± 2 vs. low GM1 = 12.1 ± 0.5, p < 0.01), suggesting that the presence of GM1 in the membrane can modulate the distribution and the membrane perforation by Aβ. On the other hand, increasing GM1 facilitated the membrane perforation (TEPC: control = 7.8 ± 2 vs. GM1 = 6.2 ± 1 min, p < 0.05). Additionally, using Cholera Toxin Subunit-B (CTB) to block the interaction of Aβ with GM1 attenuated membrane perforation significantly. Furthermore, …

Evaluating The Therapeutic Effect Of An Hsp90 Inhibitor In Mouse Models Of Alzheimer’S Disease, Bin Wang

Theses and Dissertations (ETD)

The excessive accumulation of amyloid peptides (Aβ) represents one major pathological hallmark of Alzheimer’s disease (AD), which is most notably characterized by synaptic dysfunction. Strategies targeting heat shock protein 90 (Hsp90) inhibition have been widely investigated in the treatment of cancer for over two decades. Its application in the treatment of neurodegenerative diseases however, has emerged more recently in the last decade. The role of the Hsp90 chaperone in clearing misfolded protein aggregates has been well established (in vitro only), but its function in synaptic activity remains elusive.

In our study, we utilized a widely used Hsp90 inhibitor, 17-AAG …

The Semantic Memory Imaging In Late Life Pilot Study, Michael Adam Sugarman

Wayne State University Dissertations

Introduction: Several functional magnetic resonance imaging (fMRI) studies have analyzed the famous name discrimination task (FNDT), an uncontrolled semantic memory probe requiring discrimination between famous and unfamiliar individuals. Completion of this simple task recruits a semantic memory network that has shown utility in determining risk for Alzheimer's disease (AD). Specific semantic memory probes using biographical information associated with famous individuals may build on previous findings and yield superior information regarding risk for AD.

Method: Sixteen cognitively intact elders completed the FNDT and two novel tasks during fMRI: Categories (matching famous individuals to occupational categories) and Attributes (matching famous individuals to …

Comparing Biological Markers Of Alzheimer's Disease Across Blood Fraction And Platforms: Comparing Apples To Oranges, Sid E. O'Bryant, Simone Lista, Robert A. Rissman, Melissa Edwards, Fan Zhang, James Hall, Herik Zetterberg, Simon Lovestone, Veer Bular Gupta, Neill Graff-Radford, Ralph N. Martins, Andreas Jeromin, Stephen Waring, Esther Oh, Mitchel Kling, Laura D. Baker, Harald Hampel

Research outputs 2014 to 2021

Introduction:

This study investigated the comparability of potential Alzheimer's disease (AD) biomarkers across blood fractions and assay platforms.

Methods:

Nonfasting serum and plasma samples from 300 participants (150 AD patients and 150 controls) were analyzed. Proteomic markers were obtained via electrochemiluminescence or Luminex technology. Comparisons were conducted via Pearson correlations. The relative importance of proteins within an AD diagnostic profile was examined using random forest importance plots.

Results:

On the Meso Scale Discovery multiplex platform, 10 of the 21 markers shared > 50% of the variance across blood fractions (serum amyloid A R2 = 0.99, interleukin (IL)10 R2 = 0.95, fatty …

Finding Chemopreventatives To Reduce Amyloid Beta In Yeast, Ian Macreadie, Costa Arvanitis, Prashant Bharadwaj

Research outputs 2014 to 2021

Alzheimer's disease (AD) is the most common form of age-related dementia with the latest report (WorldAlzheimerReport, 2015) showing 46.8 million people are currently affected by dementia. That number is expected to double every 20 years unless there is effective therapeutic intervention.

The Therapeutic Role Of Turmeric In Treatment And Prevention Of Alzheimer’S Disease, Rylan M. Mcquade

Selected Honors Theses

As a devastating neurological condition that expends millions of lives each year, Alzheimer’s disease (AD) is a subject of intense investigation.¹ Although AD has been known for over a century, the precise mechanisms that underlie AD pathogenesis and development are still poorly understood. The Alzheimer phenotype is typified by extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), causing researchers to notice several key enzymes implicated in this process.¹ Most notable are β and γ secretases (which drive Aβ plaque production) and phospholipase

A₂ (which stimulates major cascade activation through the specific cleavage of fatty acyl esters). …

The Effect Of Acute Lps-Induced Immune Activation And Brain Insulin Signaling Disruption In A Diabetic Model Of Alzheimer's Disease, Andrew Scott Murtishaw

UNLV Theses, Dissertations, Professional Papers, and Capstones

Alzheimer's disease (AD) is a neurodegenerative disorder marked by progressive cognitive impairments and pathological hallmarks that include amyloid plaques, neurofibrillary tangles, and neuronal loss. Several well-known mutations exist that lead to early-onset familial AD (fAD). However, these cases only account for a small percentage of total AD cases. The vast majority of AD cases are sporadic in origin (sAD) and are less clearly influenced by a single mutation but rather some combination of genetic and environmental risk.

The etiology of sAD remains unclear but numerous risk factors have been identified that increase the chance of developing AD. Among these risk …

The End Of Alzheimer's Disease - From Biochemical Pharmacology To Ecopsychosociology: A Personal Perspective, Peter J. Whitehouse

Faculty Scholarship

The future of the Alzheimer's disease (AD) field involves a more complete understanding not only the state of current scientific approaches, but also the linguistic and cultural context of preclinical and clinical research and policy activities. The challenges surrounding dementia are large and growing but are only part of broader social and health concerns. In this latter context, the current state of research in the AD area is reviewed together with necessary priorities in moving forward. Creating a more optimistic future will depend less on genetic and reductionist approaches and more on environmental and intergenerative approaches that will aid in …

Nature Of The Neurotoxic Membrane Actions Of Amyloid-Β On Hippocampal Neurons In Alzheimer's Disease, Fernando J. Sepúlveda, Humberto Fierro, Eduardo Fernandez, Carolina Castillo, Robert W. Peoples, Carlos Opazo, Luis G. Aguayo

Biomedical Sciences Faculty Research and Publications

The mechanism by which amyloid-β (Aβ) produces brain dysfunction in patients with Alzheimer's disease is largely unknown. According to previous studies, Aβ might share perforating properties with gramicidin, a well-accepted membrane-disrupting peptide. Therefore, we hypothesize that the key steps leading to synaptotoxicity by Aβ and gramicidin involve peptide aggregation, pore formation, and calcium dysregulation. Here, we show that Aβ and gramicidin form aggregates enriched in β-sheet structures using electron microscopy, and Thioflavin and Congo Red staining techniques. Also, we found that Aβ and gramicidin display fairly similar actions in hippocampal cell membranes, i.e. inducing Ca²⁺ entry and synaptoxicity characterized …

Altered Cytological Parameters In Buccal Cells From Individuals With Mild Cognitive Impairment And Alzheimer's Disease, Maxime François, Wayne Leifert, Jane Hecker, Jeffrey Faunt, Ralph Martins, Philip Thomas, Michael Fenech

Research outputs 2014 to 2021

Previous studies have shown that mild cognitive impairment (MCI) may be reflective of the early stages of more pronounced neurodegenerative disorders such as Alzheimer's disease (AD). There is a need for a minimally invasive and inexpensive diagnostic to identify those who exhibit cellular pathology indicative of MCI and AD risk so that they can be prioritized for primary preventative measures. The hypothesis was that a minimally invasive approach using cytological markers in isolated buccal mucosa cells can be used to identify individuals of both MCI and AD. An automated buccal cell assay was developed using laser scanning cytometry (LSC) to …

Impact Of Nutrition On Cognition And Its Association With Blood And Brain Alzheimer Disease Related Biomarkers, Samantha Gardener

Theses: Doctorates and Masters

Alzheimer’s disease (AD), the most common form of senile dementia, currently affects over 35 million people worldwide. While there is no cure or effective treatment, early intervention programs hold considerable promise. Following particular dietary patterns represents one potential intervention strategy accessible to all.

Results from previous studies investigating the association of diet, cognition and biomarkers of AD are inconsistent: Positive results have been reported (1-7), whilst others have shown no associations. Prior to this thesis, no study has assessed the relationship of four dietary patterns to cognition, blood-based and neuroimaging biomarkers of AD in a large highly-characterised ageing cohort. Participants …

Biomarkers Of Alzheimer's Disease Risk In Peripheral Tissues; Focus On Buccal Cells, Maxime François, Wayne Leifert, Ralph Martins, Philip Thomas, Michael Fenech

Research outputs 2014 to 2021

Alzheimer's disease (AD) is a progressive degenerative disorder of the brain and is the most common form of dementia. To-date no simple, inexpensive and minimally invasive procedure is available to confirm with certainty the early diagnosis of AD prior to the manifestations of symptoms characteristic of the disease. Therefore, if population screening of individuals is to be performed, more suitable, easily accessible tissues would need to be used for a diagnostic test that would identify those who exhibit cellular pathology indicative of mild cognitive impairment (MCI) and AD risk so that they can be prioritized for primary prevention. This need …

Intracranial Injection Of Gammagard, A Human Ivig, Modulates The Inflammatory Response Of The Brain And Lowers AΒ In App/Ps1 Mice Along A Different Time Course Than Anti-AΒ Antibodies, Tiffany L. Sudduth, Abigail Greenstein, Donna M. Wilcock

Sanders-Brown Center on Aging Faculty Publications

Gammagard IVIg is a therapeutic approach to treat Alzheimer's disease currently in phase 3 clinical trials. Despite the reported efficacy of the approach the mechanism of action is poorly understood. We have previously shown that intracranial injection of anti-Aβ antibodies into the frontal cortex and hippocampus reveals important information regarding the time course of events once the agent is in the brain. In the current study we compared IVIg, mouse-pooled IgG, and the anti-Aβ antibody 6E10 injected intracranially into the frontal cortex and hippocampus of 7-month-old APP/PS1 mice. We established a time course of events ranging from 1 …

The Effects Of Chronic Calcium Dysregulation On Behavioral And Pathological Features Of Alzheimer's Disease, Jonathan Sabbagh

UNLV Theses, Dissertations, Professional Papers, and Capstones

Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose etiology is unknown. Recent studies have implicated alterations in calcium homeostasis as a pathogenic contributor to AD. Calcium dysregulation has been observed in aged and AD brains, an event which could potentially facilitate the development of multiple pathologies observed in AD. Specifically, disrupting intracellular calcium levels in vitro has been demonstrated to increase amyloid-beta (Aβ) production, tau phosphorylation, and neuronal loss. However, there is a paucity of data on the behavioral and biochemical consequences of chronic in vivo perturbation of calcium homeostasis. In a series of experiments designed to evaluate the …

A Study Of Small Rnas From Cerebral Neocortex Of Pathology-Verified Alzheimer's Disease, Dementia With Lewy Bodies, Hippocampal Sclerosis, Frontotemporal Lobar Dementia, And Non-Demented Human Controls, Sébastien S. Hébert, Wang-Xia Wang, Qi Zhu, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

MicroRNAs (miRNAs) are small (20-22 nucleotides) regulatory non-coding RNAs that strongly influence gene expression. Most prior studies addressing the role of miRNAs in neurodegenerative diseases (NDs) have focused on individual diseases such as Alzheimer's disease (AD), making disease-to-disease comparisons impossible. Using RNA deep sequencing, we sought to analyze in detail the small RNAs (including miRNAs) in the temporal neocortex gray matter from non-demented controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent …

Electronic Properties Of Memantine (Alzheimer's Disease) And Amantadine (Anti-Flu) Drugs, Kirsten Middleton, Guo-Ping Zhang, Thomas F. George

Symposium 2012

Alzheimer’s Disease is the 5th leading cause of death for Americans 65 and older Treatment The U.S. Food and Drug Administration Only five drugs approved that “temporarily slow worsening of symptoms for about six to 12 months.” Effective for only about half of all patients.

Neuron To Microglia Communication; A Study Of Cx3cl1 Signaling Implications In Cognitive Function, Inflammation, And Neurodegeneration, Joshua M. Morganti

USF Tampa Graduate Theses and Dissertations

As a consequence of aging, the brain is subject to chronic neuroinflammatory conditions. The resident immune cells of the brain, microglia, act similarly to peripheral macrophages to protect the brain from insults, infection, and physical trauma. However, without proper regulation of their respective host defense mechanisms, these actions can become neurotoxic. In the healthy brain neurons have several signaling systems that directly interact with microglia in order to maintain a calming influence upon their actions, one of particular interest is the chemokine CX3CL1. This chemokine is found predominantly on neurons, while its cognate receptor CX3CR1 is found exclusively on microglia. …

Multiple Γ-Secretase Product Peptides Are Coordinately Increased In Concentration In The Cerebrospinal Fluid Of A Subpopulation Of Sporadic Alzheimer's Disease Subjects, Saori Hata, Miyako Taniguchi, Yi Piao, Takeshi Ikeuchi, Anne Fagan, David Holtzman, Randall Bateman, Hamid Sohrabi, Ralph Martins, Sam Gandy, Katsuya Urakami, Toshiharu Suzuki

Research outputs 2012

Background: Alcadeinα (Alcα) is a neuronal membrane protein that colocalizes with the Alzheimer's amyloid-β precursor protein (APP). Successive cleavage of APP by β- and γ-secretases generates the aggregatable amyloid-β peptide (Aβ), while cleavage of APP or Alcα by α- and γ-secretases generates non-aggregatable p3 or p3-Alcα peptides. Aβ and p3-Alcα can be recovered from human cerebrospinal fluid (CSF). We have previously reported alternative processing of APP and Alcα in the CSF of some patients with sporadic mild cognitive impairment (MCI) and AD (SAD). Results: Using the sandwich enzyme-linked immunosorbent assay (ELISA) system that detects total p3-Alcα, we determined levels of …

Focus On Rna Isolation: Obtaining Rna For Microrna (Mirna) Expression Profiling Analyses Of Neural Tissue, Wang-Xia Wang, Bernard R. Wilfred, Donald A. Baldwin, R. Benjamin Isett, Na Ren, Arnold J. Stromberg, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

MicroRNAs (miRNAs) are present in all known plant and animal tissues and appear to be somewhat concentrated in the mammalian nervous system. Many different miRNA expression profiling platforms have been described. However, relatively little research has been published to establish the importance of 'upstream' variables in RNA isolation for neural miRNA expression profiling. We tested whether apparent changes in miRNA expression profiles may be associated with tissue processing, RNA isolation techniques, or different cell types in the sample. RNA isolation was performed on a single brain sample using eight different RNA isolation methods, and results were correlated using a conventional …

Β-N-Methylamino-L-Alanine Enhances Neurotoxicity Through Multiple Mechanisms, Doug Lobner, Peachy Mae T. Piana, Abed K. Salous, Robert W. Peoples

Biomedical Sciences Faculty Research and Publications

The idea that the environmental toxin β-N-methylamino-l-alanine (BMAA) is involved in neurodegenerative diseases on Guam has risen and fallen over the years. The theory has gained greater interest with recent reports that BMAA is biomagnified, is widely distributed around the planet, and is present in the brains of Alzheimer's patients in Canada. We provide two important new findings. First, we show that BMAA at concentrations as low as 10 μM can potentiate neuronal injury induced by other insults. This is the first evidence that BMAA at concentrations below the mM range can enhance death of cortical neurons and …

Structural Mri Discriminates Individuals With Mild Cognitive Impairment From Age-Matched Controls: A Combined Neuropsychological And Voxel Based Morphometry Study, Mehul A. Trivedi, Allison K. Wichmann, Britta M. Torgerson, Michael A. Ward, Taylor W. Schmitz, Michele L. Ries, Rebecca L. Koscik, Sanjay Asthana, Sterling C. Johnson

Brain and Mind Institute Researchers' Publications

Background: Several previous studies have reported that amnestic mild cognitive impairment (aMCI), a significant risk factor for Alzheimer's disease (AD), is associated with greater atrophy in the medial temporal lobe (MTL) and posterior cingulate gyrus (PCG). Method: In the present study, we examined the cross-sectional accuracy (i.e., the sensitivity and specificity) of voxel-based morphometry (VBM) in discriminating individuals with MCI (n = 15) from healthy age-matched controls (n = 15). In addition, we also sought to determine whether baseline GM volume predicted aMCI patients that converted to AD from those that did not approximately 2 years after the baseline visit. …

Vinpocetine For Cognitive Impairment And Dementia, Peter J. Whitehouse

Faculty Scholarship

Background: Vinpocetine is a synthetic ethyl ester of apovincamine, a vinca alkaloid obtained from the leaves of the Lesser Periwinkle (Vinca minor) and discovered in the late 1960s. Although used in human treatment for over twenty years, it has not been approved by any regulatory body for the treatment of cognitive impairment. Basic sciences studies have been used to claim a variety of potentially important effects in the brain. However, despite these many proposed mechanisms and targets, the relevance of this basic science to clinical studies is unclear. Objectives: To assess the efficacy and safety of vinpocetine in the treatment …

Ethical Issues In Dementia, Peter J. Whitehouse

Faculty Scholarship

The growing number of individuals affected by dementia will intensify the ethical issues that emerge in clinical practice and research, issues early in disease relate to genetic testing, use of medications in mildly affected persons, and diagnostic disclosure. Research issues relate to appropriate informed consent processes, conflict of interests, and research design issues, such as the use of placebos and the use of biological tissues. In the later stages of disease concern about appropriate therapeutic goals and end-of-life care is appropriate.