Medicine and Health Sciences Commons^™

Impact Of Interleukin-34 On The Promotion Of Bone Osteolysis And Neuroinflammation In Experimental Models Of Alzheimer’S Disease, Anny Ho

All HCAS Student Capstones, Theses, and Dissertations

Alzheimer’s disease (AD) is a growing health concern and is the most common type of dementia worldwide. Emerging evidence indicates that aggregated amyloid-beta (Aβ) peptides, one of the hallmark features of AD neuropathology, can increase RANKL-mediated osteoclast activity leading to the prevalence and severity of inflammatory osteolysis, e.g., osteoporosis and periodontal bone loss. Conversely, osteolytic lesions are associated with increased risk of dementia diagnosis indicating that there is a direct link between dementia and inflammatory osteolysis. It was demonstrated that the neuronal cells primarily produce interleukin-34 (IL-34) and microglia, macrophages, and osteoclast precursors express colony-stimulating factor 1 receptor (CSF-1R), a …

New Evidence For P-Gp-Mediated Export Of Amyloid-Β Peptides In Molecular, Blood-Brain Barrier And Neuronal Models, Amanda B. Chai, Anika M. S. Hartz, Xuexin Gao, Alryel Yang, Richard Callaghan, Ingrid C. Gelissen

Sanders-Brown Center on Aging Faculty Publications

Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aβ) peptides in the Alzheimer’s brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. The ability for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, to export Aβ across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp–Aβ interaction persist. Here, molecular data affirm that both Aβ₄₀ and Aβ₄₂ peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the …

Potential Of Sorghum Polyphenols To Prevent And Treat Alzheimer's Disease: A Review Article, Nasim Rezaee, Warnakulasuriya Mary Ann Dipika Fernando, Eugene Hone, Hamid R. Sohrabi, Stuart K. Johnson, Stuart Gunzburg, Ralph Martins

Research outputs 2014 to 2021

Alzheimer’s disease (AD) is characterized by the excessive deposition of extracellular amyloid-beta peptide (Aβ) and the build-up of intracellular neurofibrillary tangles containing hyperphosphorylated tau proteins. This leads to neuronal damage, cell death and consequently results in memory and learning impairments leading to dementia. Although the exact cause of AD is not yet clear, numerous studies indicate that oxidative stress, inflammation, and mitochondrial dysfunction significantly contribute to its onset and progression. There is no effective therapeutic approach to stop the progression of AD and its associated symptoms. Thus, early intervention, preferably, pre-clinically when the brain is not significantly affected, is a …

Somatosensory Dysfunction Is Masked By Variable Cognitive Deficits Across Patients On The Alzheimer’S Disease Spectrum, Alex I. Wiesman, Victoria M. Mundorf, Chloe C. Casagrande, Sara L. Wolfson, Craig M. Johnson, Pamela E. May, Daniel L. Murman, Tony W. Wilson

Center for Brain, Biology, and Behavior: Faculty and Staff Publications

Background: Alzheimer’s disease (AD) is generally thought to spare primary sensory function; however, such interpretations have drawn from a literature that has rarely taken into account the variable cognitive declines seen in patients with AD. As these cognitive domains are now known to modulate cortical somato-sensory processing, it remains possible that abnormalities in somatosensory function in patients with AD have been suppressed by neuropsychological variability in previous research. Methods: In this study, we combine magnetoencephalographic (MEG) brain imaging during a paired-pulse somatosensory gating task with an extensive battery of neuropsychological tests to investigate the influence of cognitive variability on estimated …

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 …

The Role Of Atf4 In Amyloid-Beta-Induced Neuronal Death., Gillian Petroff

Electronic Thesis and Dissertation Repository

Alzheimer’s disease (AD) is partially characterized by excessive accumulation of amyloid-b (Ab) in the brain. Ab oligomers have greater toxicity than Ab fibrils and induce neuronal stress. The Integrated Stress Response (ISR) is activated in response to cellular stress and increases expression of activating transcription factor 4 (ATF4) and its target genes. Prolonged activation has been shown to induce aberrant cell death, and increased markers of the ISR have been found in the brains of AD patients. However, the exact mechanism of amyloid-b-induced death is largely unknown. We aimed to determine if Ab-induced neuronal death occurs through ATF4-mediated upregulation of …

Plasma Neurofilament Light Chain And Amyloid-Β Are Associated With The Kynurenine Pathway Metabolites In Preclinical Alzheimer's Disease, Pratishtha Chatterjee, Henrik Zetterberg, Kathryn Goozee, Chai K. Lim, Kelly R. Jacobs, Nicholas J. Ashton, Abdul Hye, Steve Pedrini, Hamid R. Sohrabi, Tejal Shah, Prita R. Asih, Preeti Dave, Kaikai Shen, Kevin Taddei, David B. Lovejoy, Gilles J. Guillemin, Kaj Blennow, Ralph N. Martins

Research outputs 2014 to 2021

BACKGROUND: Blood markers indicative of neurodegeneration (neurofilament light chain; NFL), Alzheimer's disease amyloid pathology (amyloid-β; Aβ), and neuroinflammation (kynurenine pathway; KP metabolites) have been investigated independently in neurodegenerative diseases. However, the association of these markers of neurodegeneration and AD pathology with neuroinflammation has not been investigated previously. Therefore, the current study examined whether NFL and Aβ correlate with KP metabolites in elderly individuals to provide insight on the association between blood indicators of neurodegeneration and neuroinflammation.

METHODS: Correlations between KP metabolites, measured using liquid chromatography and gas chromatography coupled with mass spectrometry, and plasma NFL and Aβ concentrations, measured using …

Investigating The Rho-Kinase (Rock) Signaling Pathway As A Therapeutic Target In Alzheimer’S Disease, Benjamin Wade Henderson

All ETDs from UAB

Current estimates project that there are approximately 5.4 million Americans affected by Alzheimer’s disease (AD). While this number is expected to dramatically increase in the years to come, there is currently no disease modifying therapeutic to prevent or slow AD progression. Cognitive decline is a clinical hallmark of AD, while accumulation of amyloid-β (Aβ) is a pathological hallmark. Work in the field has demonstrated that mitigating Aβ levels may serve as a rational therapeutic avenue to slow progression of the disease. Pharmacologic inhibition of the Rho-associated protein kinases (ROCK1 and ROCK2) is proposed to curb Aβ levels, and mechanisms that …

Cause And Consequence Of Aβ: Lipid Interactions In Alzheimer Disease Pathogenesis, Vijay Rangachari, Dexter N. Dean, Pratip Rana, Ashwin Vaidya, Preetam Ghosh

Faculty Publications

Self-templating propagation of protein aggregate conformations is increasingly becoming a significant factor in many neurological diseases. In Alzheimer disease (AD), intrinsically disordered amyloid-β (Aβ) peptides undergo aggregation that is sensitive to environmental conditions. High-molecular weight aggregates of Aβ that form insoluble fibrils are deposited as senile plaques in AD brains. However, low-molecular weight aggregates called soluble oligomers are known to be the primary toxic agents responsible for neuronal dysfunction. The aggregation process is highly stochastic involving both homotypic (Aβ-Aβ) and heterotypic (Aβ with interacting partners) interactions. Two of the important members of interacting partners are membrane lipids and surfactants, to …

An Isogenic Stem Cell Model Of Alzheimer's Disease: Direct Expression Of Amyloid-Beta, Teresa Marie Ubina

Electronic Theses, Projects, and Dissertations

Alzheimer’s disease (AD), identified over 100 years ago and intensively studied since the 1970s, has no effective treatments or mechanistic understanding of the underlying neurodegenerative process. Most investigators believe accumulation or aggregation of amyloid beta (Ab) proteins plays a causative role. Aβ peptides (~39-43 residues) are generated by proteolysis of the transmembrane protein APP. One reason we know so little about AD is an incomplete understanding of the cellular mechanisms responsible for Ab proteotoxicity. Human ES and iPSC models of AD are recent additions to many other models used to investigate these mechanisms. AD, however is a chronic progressive condition …

Light Dependent Endolysosomal Defects In A Photoreceptor Model Of Alzheimer's Disease, Michelle S. Smith

Undergraduate Honors Theses

Alzheimer’s disease (AD) is a neurodegenerative disease which is the 6^th leading cause of death in the US. AD pathology is thought to be linked to the accumulation and aggregation of toxic proteins, amyloid-beta and tau. AD development and neurodegeneration is proposed to be caused by the toxic effects of these protein accumulations, specifically amyloid-beta, as postulated by the amyloid-cascade hypothesis. To study the relationship between amyloid-beta and overall neuronal health, a study was carried out using an amyloid-expressing fruit fly photoreceptor model. Using this model, toxicity of amyloid in a stressed lysosomal system induced by light, an established …

Cerebral Lactate Metabolism And Memory: Implications For Alzheimer's Disease, Richard Andrew Harris

Electronic Thesis and Dissertation Repository

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by amyloid plaques that are comprised of aggregated amyloid-beta peptides. These toxic proteins promote mitochondrial dysfunction and neuronal cell death. A shift in metabolism away from oxidative phosphorylation and toward aerobic glycolysis, with the concomitant production of lactate, affords neurons a survival advantage against amyloid-beta toxicity. Recent evidence now suggests that aerobic glycolysis in the brain plays a critical role in supporting synaptic plasticity, learning, and memory. However, the role of aerobic glycolysis and lactate metabolism in AD-mediated cognitive decline is unknown. My objective was to test the hypotheses that aerobic glycolysis …

The Concerted Regulation Of Intracellular Signaling By Amyloid Precursor Protein And Aβ Peptide, Lisa Kirouac

USF Tampa Graduate Theses and Dissertations

It is widely accepted that A-beta (Aβ) generated from amyloid precursor protein (APP) oligomerizes and fibrillizes to form neuritic plaques in the Alzheimer’s disease (AD) brain, yet little is known about the contribution of APP preceding AD pathogenesis. Our data presented here suggest that APP has a functional role in cell cycle regulation and proliferation. First, we demonstrat that APP is pathologically phosphorylated at Thr₆₆₈ and that P-APP localizes to the centrosomes. Furthermore, P-APP is proteolytically processed in a cell cycle -dependent manner to generate its pathogenic metabolites. Using Stable Isotope Labeling by Amino Acids in Culture (SILAC) and …

The Level Of Nmda Receptor In The Membrane Modulates Amyloid-Β Association And Perforation, Christian Peters, Fernando J. Sepúlveda, Eduardo Fernández-Pérez, Robert W. Peoples, Luis G. Aguayo

Biomedical Sciences Faculty Research and Publications

Alzheimer’s disease is a neurodegenerative disorder that affects mostly the elderly. The main histopathological markers are the senile plaques formed by amyloid-β peptide (Aβ) aggregates that can perforate the plasma membrane of cells, increasing the intracellular calcium levels and releasing synaptic vesicles that finally lead to a delayed synaptic failure. Several membrane proteins and lipids interact with Aβ affecting its toxicity in neurons. Here, we focus on NMDA receptors (NMDARs) as proteins that could be modulating the association and neurotoxic perforation induced by Aβ on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA …

The Effects Of Latrepirdine On Amyloid-Β Aggregation And Toxicity, Tenielle Porter, Prashant Bharadwaj, David Groth, Adrian Paxman, Simon Laws, Ralph Martins, Guiseppe Verdile

Research outputs 2014 to 2021

Latrepirdine (DimebonTM) has been demonstrated to be a neuroprotective and cognition improving agent in neurodegenerative diseases that feature protein aggregation and deposition, such as Alzheimer's disease (AD). The accumulation of amyloid-β (Aβ) protein aggregates is a key event in the neurodegenerative process in AD. This study explores if latrepirdine modulation of protein aggregation contributes to its neuroprotective mechanism of action. Assessment of neuronal cell death showed that there was a significant reduction in lactate dehydrogenase release at an equimolar ratio of Aβ:latrepirdine and with lower concentrations of latrepirdine. The ability of latrepirdine to alter the formation of Aβ42 aggregates was …

Deletion Of Aquaporin-4 In App/Ps1 Mice Exacerbates Brain Aβ Accumulation And Memory Deficits, Zhiqiang Xu, Na Xiao, Yali Chen, Huang Huang, Charles Marshall, Junying Gao, Zhiyou Cai, Ting Wu, Gang Hu, Ming Xiao

Center of Excellence in Rural Health Faculty Publications

BACKGROUND: Preventing or reducing amyloid-beta (Aβ) accumulation in the brain is an important therapeutic strategy for Alzheimer's disease (AD). Recent studies showed that the water channel aquaporin-4 (AQP4) mediates soluble Aβ clearance from the brain parenchyma along the paravascular pathway. However the direct evidence for roles of AQP4 in the pathophysiology of AD remains absent.

RESULTS: Here, we reported that the deletion of AQP4 exacerbated cognitive deficits of 12-moth old APP/PS1 mice, with increases in Aβ accumulation, cerebral amyloid angiopathy and loss of synaptic protein and brain-derived neurotrophic factor in the hippocampus and cortex. Furthermore, AQP4 deficiency increased …

Stress Granules Modulate Syk To Cause Microglial Cell Dysfunction In Alzheimer's Disease, Soumira Ghosh, Robert Geahlen

Department of Medicinal Chemistry and Molecular Pharmacology Faculty Publications

Microglial cells in the brains of Alzheimer's patients are known to be recruited to amyloid-beta (Aβ) plaques where they exhibit an activated phenotype, but are defective for plaque removal by phagocytosis. In this study, we show that microglia stressed by exposure to sodium arsenite or Aβ(1–42) peptides or fibrils form ex- tensive stress granules (SGs) to which the tyrosine kinase, SYK, is recruited. SYK enhances the formation of SGs, is active within the resulting SGs and stimulates the production of reactive oxygen and nitrogen species that are toxic to neuronal cells. This sequestration of SYK inhibits the ability of microglial …

Strategies For Preventing Age And Neurodegenerative Disease-Associated Mitochondrial Dysfunction, Vedad Delic

USF Tampa Graduate Theses and Dissertations

Mitochondrial dysfunction plays a pivotal role in the development of aging phenotypes and aging-associated neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS). Strategies that restore mitochondrial dysfunction may rescue the deficits of central metabolism in these disorders and improve cell survival. For example, we found that modulating the mTOR signaling pathway in a tissue culture model of aging-induced mitochondrial DNA mutation enhanced mitochondrial function as evidenced by increased oxygen consumption. Our previous melatonin studies also led us to hypothesize that caloric restriction and the hormone melatonin would reverse brain mitochondrial dysfunction in animal …

The Molecular Interaction Between Type Ii Diabetes And Alzheimer’S Disease Through Cross-Seeding Of Protein Misfolding, George A. Edwards Iii

Dissertations & Theses (Open Access)

With the population of the world aging, the prominence of diseases such as Type II Diabetes (T2D) and Alzheimer’s disease (AD) are on the rise. In addition, patients with T2D have an increased risk of developing AD compared to age-matched individuals, and the number of AD patients with T2D is higher than among aged-matched non-AD patients. AD is a chronic and progressive dementia characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs), neuronal loss, brain inflammation, and cognitive impairment. T2D involves the dysfunctional use of pancreatic insulin by the body resulting in insulin resistance, hyperglycemia, hyperinsulinemia, pancreatic beta cell (β-cell) death, …

Proteolytic Processing Of The Amyloid Precursor Protein During Apoptosis And Cell Cycle: Implications For Alzheimer's Disease, Tina N. Fiorelli

USF Tampa Graduate Theses and Dissertations

Alzheimer's disease is characterized by the presence of amyloid plaques, made up primarily of Aϐ peptides, and neurofibrillary tangles, containing hyperphosphorylated tau. Aϐ is generated by sequential proteolysis of the amyloid precursor protein (APP) by beta and gamma secretases. The leading hypothesis of Alzheimer's disease pathogenesis is the amyloid cascade hypothesis, which suggests that amyloid is central to the disease process. However, tau pathology correlates more closely with cognitive dysfunction and follows a predictable anatomical course through the brain. We hypothesize that if Aϐ is upstream of tau pathology and tau pathology follows this predictable course through the brain, Aϐ …