{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/124674"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/124674","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"The investigation of the neuronal and synaptic defects in early stage of amyloid-beta pathology","abstract":"Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the progressive loss of neural cells and subsequent cognitive dysfunction, making it the primary cause of dementia. Previous studies have predominantly focused on brain hypoactivity caused by the toxic aggregation of amyloid beta (A) plaques and neurofibrillary tangles so far. However, emerging evidence suggests that hyperexcitability precedes other symptoms by decades in patients and further accelerates the disease progression. Interestingly, treatment with an antiepileptic drug, levetiracetam, has shown promise in slowing down cognitive decline in both patients and mouse models, indicating potential therapeutic benefits. Nevertheless, this paradigm shift still requires further investigation into the molecular basis behind the initiation of hyperexcitability in the preclinical stage and its transition to hypoactivity to develop therapeutic approaches for AD. We hypothesized that A accumulation may drive hyperexcitability in the early pathology because A starts deposition without tauopathy at this stage. As demonstrated in Chapter 2, our study elucidates the molecular mechanism by which A elevates postsynaptic density protein 95 (PSD-95), promoting seizure response in young APP/PS1 mice. This elevation results from reduced ubiquitination caused by Akt-dependent phosphorylation of E3 ubiquitin ligase murine-double-minute 2 (Mdm2). PSD-95 is required for facilitating excitatory synapses and the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors induced by Aβ. Inhibition of PSD-95 corrects these Aβ-induced synaptic defects and alleviates seizure activity in APP/PS1 mice, underscoring its potential as an early biomarker and novel therapeutic target for AD. Excitotoxicity, induced by prolonged excitation, leads to neuronal damage and death, potentially contributing to the transition from hyper- to hypoactivity in AD. This process activates activating transcription factor 4 (ATF4), a molecular switch between pro-survival and pro-death pathways, whose upregulation in AD patients and mouse models suggests its involvement in this transition. In Chapter 3, we characterize the role of ATF4 in neuronal network activity and mouse behaviors, finding that ATF4+/- neurons exhibit reduced spontaneous spike rate, burst frequency, and synchronicity. These changes correlate with memory impairment rather than seizure severity, highlighting ATF4 as a necessary component in learning and memory performance. This suggests the potential role of ATF4 in learning and memory impairment in AD, warranting further research. Taken together, this dissertation offers novel insights into early AD pathology, highlighting the roles of PSD-95 and ATF4, thereby paving the way for innovative therapeutic strategies.","abstract_html":"Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the progressive loss of neural cells and subsequent cognitive dysfunction, making it the primary cause of dementia. Previous studies have predominantly focused on brain hypoactivity caused by the toxic aggregation of amyloid beta (A) plaques and neurofibrillary tangles so far. However, emerging evidence suggests that hyperexcitability precedes other symptoms by decades in patients and further accelerates the disease progression. Interestingly, treatment with an antiepileptic drug, levetiracetam, has shown promise in slowing down cognitive decline in both patients and mouse models, indicating potential therapeutic benefits. Nevertheless, this paradigm shift still requires further investigation into the molecular basis behind the initiation of hyperexcitability in the preclinical stage and its transition to hypoactivity to develop therapeutic approaches for AD. We hypothesized that A accumulation may drive hyperexcitability in the early pathology because A starts deposition without tauopathy at this stage. As demonstrated in Chapter 2, our study elucidates the molecular mechanism by which A elevates postsynaptic density protein 95 (PSD-95), promoting seizure response in young APP/PS1 mice. This elevation results from reduced ubiquitination caused by Akt-dependent phosphorylation of E3 ubiquitin ligase murine-double-minute 2 (Mdm2). PSD-95 is required for facilitating excitatory synapses and the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors induced by Aβ. Inhibition of PSD-95 corrects these Aβ-induced synaptic defects and alleviates seizure activity in APP/PS1 mice, underscoring its potential as an early biomarker and novel therapeutic target for AD. Excitotoxicity, induced by prolonged excitation, leads to neuronal damage and death, potentially contributing to the transition from hyper- to hypoactivity in AD. This process activates activating transcription factor 4 (ATF4), a molecular switch between pro-survival and pro-death pathways, whose upregulation in AD patients and mouse models suggests its involvement in this transition. In Chapter 3, we characterize the role of ATF4 in neuronal network activity and mouse behaviors, finding that ATF4+/- neurons exhibit reduced spontaneous spike rate, burst frequency, and synchronicity. These changes correlate with memory impairment rather than seizure severity, highlighting ATF4 as a necessary component in learning and memory performance. This suggests the potential role of ATF4 in learning and memory impairment in AD, warranting further research. Taken together, this dissertation offers novel insights into early AD pathology, highlighting the roles of PSD-95 and ATF4, thereby paving the way for innovative therapeutic strategies.","abstract_has_math":false,"creators":["Yook, Yeeun"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Molecular & Integrative Physi","degree_department":null,"school":null,"contributors":["Tsai, Nien-Pei","Ceman, Stephanie S","Chung, Hee Jung","Christian-Hinman, Catherine A"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-04-24","date_published":"2024-04-24","updated_at":"2026-07-22T22:25:02Z","subjects":["Amyloid-beta","Hyperexcitability","Seizures","Psd-95","App/ps1"],"languages":["eng","en"],"rights":["Copyright 2024 Yeeun Yook"],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2142/124674","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Tsai, Nien-Pei","Ceman, Stephanie S","Chung, Hee Jung","Christian-Hinman, Catherine A"]},{"key":"dc:creator","label":"Author","values":["Yook, Yeeun"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2024-04-24","2024-05"]},{"key":"dc:type","label":"Dc Type","values":["Text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Molecular & Integrative Physi"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Amyloid-beta","Hyperexcitability","Seizures","Psd-95","App/ps1"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng","en"]},{"key":"dc:rights","label":"Dc Rights","values":["Copyright 2024 Yeeun Yook"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2142/124674"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the progressive loss of neural cells and subsequent cognitive dysfunction, making it the primary cause of dementia. Previous studies have predominantly focused on brain hypoactivity caused by the toxic aggregation of amyloid beta (A) plaques and neurofibrillary tangles so far. However, emerging evidence suggests that hyperexcitability precedes other symptoms by decades in patients and further accelerates the disease progression. Interestingly, treatment with an antiepileptic drug, levetiracetam, has shown promise in slowing down cognitive decline in both patients and mouse models, indicating potential therapeutic benefits. Nevertheless, this paradigm shift still requires further investigation into the molecular basis behind the initiation of hyperexcitability in the preclinical stage and its transition to hypoactivity to develop therapeutic approaches for AD. We hypothesized that A accumulation may drive hyperexcitability in the early pathology because A starts deposition without tauopathy at this stage. As demonstrated in Chapter 2, our study elucidates the molecular mechanism by which A elevates postsynaptic density protein 95 (PSD-95), promoting seizure response in young APP/PS1 mice. This elevation results from reduced ubiquitination caused by Akt-dependent phosphorylation of E3 ubiquitin ligase murine-double-minute 2 (Mdm2). PSD-95 is required for facilitating excitatory synapses and the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors induced by Aβ. Inhibition of PSD-95 corrects these Aβ-induced synaptic defects and alleviates seizure activity in APP/PS1 mice, underscoring its potential as an early biomarker and novel therapeutic target for AD. Excitotoxicity, induced by prolonged excitation, leads to neuronal damage and death, potentially contributing to the transition from hyper- to hypoactivity in AD. This process activates activating transcription factor 4 (ATF4), a molecular switch between pro-survival and pro-death pathways, whose upregulation in AD patients and mouse models suggests its involvement in this transition. In Chapter 3, we characterize the role of ATF4 in neuronal network activity and mouse behaviors, finding that ATF4+/- neurons exhibit reduced spontaneous spike rate, burst frequency, and synchronicity. These changes correlate with memory impairment rather than seizure severity, highlighting ATF4 as a necessary component in learning and memory performance. This suggests the potential role of ATF4 in learning and memory impairment in AD, warranting further research. Taken together, this dissertation offers novel insights into early AD pathology, highlighting the roles of PSD-95 and ATF4, thereby paving the way for innovative therapeutic strategies.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-05-01","The student, Yeeun Yook, accepted the attached license on 2024-04-19 at 14:42.","The student, Yeeun Yook, submitted this Dissertation for approval on 2024-04-19 at 14:47.","This Dissertation was approved for publication on 2024-04-24 at 15:21.","DSpace SAF Submission Ingestion Package generated from Vireo submission #20507 on 2024-09-16 at 00:49:35"]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["The investigation of the neuronal and synaptic defects in early stage of amyloid-beta pathology"]}]}],"canonical_facts":{"dc:contributor":["Tsai, Nien-Pei","Ceman, Stephanie S","Chung, Hee Jung","Christian-Hinman, Catherine A"],"dc:creator":["Yook, Yeeun"],"dc:date":["2024-04-24","2024-05"],"dc:description":["Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the progressive loss of neural cells and subsequent cognitive dysfunction, making it the primary cause of dementia. Previous studies have predominantly focused on brain hypoactivity caused by the toxic aggregation of amyloid beta (A) plaques and neurofibrillary tangles so far. However, emerging evidence suggests that hyperexcitability precedes other symptoms by decades in patients and further accelerates the disease progression. Interestingly, treatment with an antiepileptic drug, levetiracetam, has shown promise in slowing down cognitive decline in both patients and mouse models, indicating potential therapeutic benefits. Nevertheless, this paradigm shift still requires further investigation into the molecular basis behind the initiation of hyperexcitability in the preclinical stage and its transition to hypoactivity to develop therapeutic approaches for AD. We hypothesized that A accumulation may drive hyperexcitability in the early pathology because A starts deposition without tauopathy at this stage. As demonstrated in Chapter 2, our study elucidates the molecular mechanism by which A elevates postsynaptic density protein 95 (PSD-95), promoting seizure response in young APP/PS1 mice. This elevation results from reduced ubiquitination caused by Akt-dependent phosphorylation of E3 ubiquitin ligase murine-double-minute 2 (Mdm2). PSD-95 is required for facilitating excitatory synapses and the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors induced by Aβ. Inhibition of PSD-95 corrects these Aβ-induced synaptic defects and alleviates seizure activity in APP/PS1 mice, underscoring its potential as an early biomarker and novel therapeutic target for AD. Excitotoxicity, induced by prolonged excitation, leads to neuronal damage and death, potentially contributing to the transition from hyper- to hypoactivity in AD. This process activates activating transcription factor 4 (ATF4), a molecular switch between pro-survival and pro-death pathways, whose upregulation in AD patients and mouse models suggests its involvement in this transition. In Chapter 3, we characterize the role of ATF4 in neuronal network activity and mouse behaviors, finding that ATF4+/- neurons exhibit reduced spontaneous spike rate, burst frequency, and synchronicity. These changes correlate with memory impairment rather than seizure severity, highlighting ATF4 as a necessary component in learning and memory performance. This suggests the potential role of ATF4 in learning and memory impairment in AD, warranting further research. Taken together, this dissertation offers novel insights into early AD pathology, highlighting the roles of PSD-95 and ATF4, thereby paving the way for innovative therapeutic strategies.","Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2026-05-01","The student, Yeeun Yook, accepted the attached license on 2024-04-19 at 14:42.","The student, Yeeun Yook, submitted this Dissertation for approval on 2024-04-19 at 14:47.","This Dissertation was approved for publication on 2024-04-24 at 15:21.","DSpace SAF Submission Ingestion Package generated from Vireo submission #20507 on 2024-09-16 at 00:49:35"],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2142/124674"],"dc:language":["eng","en"],"dc:rights":["Copyright 2024 Yeeun Yook"],"dc:subject":["Amyloid-beta","Hyperexcitability","Seizures","Psd-95","App/ps1"],"dc:title":["The investigation of the neuronal and synaptic defects in early stage of amyloid-beta pathology"],"dc:type":["Text"],"thesis:degree_discipline":["Molecular & Integrative Physi"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D."],"thesis:institution_name":["University of Illinois at Urbana-Champaign"]},"updated_at":"2026-07-22T22:25:02Z"}