Browsing by Subject "amyloid precursor protein"
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Item Advances in a C. elegans model of Alzheimer's disease for drug screening against neurodegeneration(2015-04) Zuniga, Gabrielle; Pierce-Shimomura, JonAlzheimer’s disease (AD) is the sixth leading cause of death in the United States, yet no treatment effectively prevents, halts or reverses the disease. Progress in developing treatments is hampered by the extensive time required for traditional mouse models of AD to age before displaying histological hallmarks of AD. We set out to test whether a novel transgenic model of AD using the nematode Caenorhabditis elegans may be used to more rapidly determine efficacy of candidate treatments through high throughput screening of behaviors. Our lab previously showed that antagonists for the conserved Sigma-2 receptor (Sig2R) are protective against age- dependent degeneration of cholinergic neurons caused by the human plaque protein, amyloid precursor protein (APP), in this model. To investigate how inhibition of Sig2R protects neurons, we tested whether knockdown of Sig2R via RNA interference prevented decline of two behaviors that depend on these cholinergic neurons. We found that RNAi treatment normalized one of the two behaviors in this AD model suggesting that the antagonists act against the Sig2R in vivo for neuroprotection. The success of this study suggests that this behavioral readout might be used to screen for additional pharmaceutical and genetic modifiers of Sig2R on neurodegeneration. In addition to developing this high throughput behavioral screening, we also built transgene components to generate an improved second generation C. elegans model of AD that conveniently tags the APP protein with mCherry for in vivo fluorescent visualization. Our results set the stage for further drug discovery using our C. elegans models of AD.Item Exploring the σ2R/TMEM97 protein‐mediated neuroprotective pathway in a C. elegans Alzheimer’s Disease Model of Neurodegeneration(2019-05-20) Shi, Ted; Pierce, JonathanAlzheimer’s disease (AD) is one of the leading causes of death in the aging population around the world. Two genetic risk factors highly correlate with and synergize in the development of AD: mutations altering copy number or processing of the amyloid precursor protein (APP) and the apolipoprotein E4 (APOE4) allelic variant. Using the genetically malleable nematode, C. elegans, we generated a strain expressing a single‐copy human APP and multiple copies of human APOE4, from which we saw progressive neurodegeneration in adulthood. We previously found that small molecule ligands of the sigma 2 receptor/transmembrane protein 97 (σ2R/TMEM97) are neuroprotective in our worm hAPP model of AD and reduce cognitive deficits in a transgenic APP mouse model. Our results suggest that a null allele of the TMEM97 gene ortholog in worm, Y38H6C.16, confers neuroprotection in our new hAPP/hAPOE4 worm model. Using this neurodegeneration model, we have also begun to screen compounds in our norbenzomorphan σ2R/TMEM97 ligand collection for the ability to influence neurodegeneration. Thus far, our findings indicate that σ2R/TMEM97 ligands can promote or inhibit neurodegeneration. To begin to understand the function of σ2R/TMEM97, we generated translational and transcriptional reporters for C. elegans. Elucidating the mechanisms underlying how σ2R/TMEM97 ligands protect against degeneration in our models is imperative in the development of treatments for uncurable neurodegenerative diseases like AD.Item Inhibiting amyloid precursor protein to prevent neurodegeneration in Down syndrome and Alzheimer's disease(2014) DeSai, Charisma; Stovall, Gwendolyn M.; Ellington, Andrew D.; Pierce-Shimomura, JonAmyloid Precursor Protein (APP) is a transmembrane integral protein concentrated in neuronal synapses. APP is cleaved by proteases into multiple peptides. One of these peptides is β-amyloid. β-amyloid peptides (amino acids 1-40, and 1-42) make up the plaques that form in the brains of Alzheimer's patients. The amyloid hypothesis suggests that reducing the amount of β-amyloid would mitigate the symptoms of Alzheimer's disease. Alzheimer's disease is the fifth leading cause of death in the US, and the only one of the top ten causes of death without an effective treatment or cure. Many patients with Down syndrome also develop Alzheimer's later in life, but earlier than normal adults. Down syndrome patients have elevated APP levels since the gene for this protein is located on chromosome 21. Almost everyone with Down syndrome develops Alzheimer's due to their extra copy of of APP. Amyloid deposition associated with Alzheimer's disease is present in all Down syndrome patients older than 30. This project targets Amyloid Precursor Protein, which is implicated in the development of Alzheimer's disease and neurodegeneration in Down syndrome, byu developing an aptamer against it. Amyloid plaques and neurofibrillary tangles form in the brain of Alzheimer's patients, and the malfunction or loss of neurons causes changes in memory and brain function. Aptamers have unique advantages for medical treatment since they are highly specific, efficiently produced, can be modified for added functions, and have very low immunogenicity. This project aims to develop an aptamer against APP to help reduce the amount of plaques by reducing its functionality and preventing the creation of β-amyloid protein. By inhibiting this pathway, the formation of amyloid plaques could be reduced or perhaps even prevented. This aptamer may even help prevent the development of dementia in people with Down syndrome as they age and individuals with familial Alzheimer's disease.