{"id":{"repo_id":"utmb","oai_identifier":"oai:utmb-ir.tdl.org:2152.3/12670"},"canonical_url":"https://search.dev.ndltd.org/etd/utmb/oai:utmb-ir.tdl.org:2152.3/12670","repository":{"repo_id":"utmb","name":"University of Texas Medical Branch","base_url":"https://utmb-ir.tdl.org/server/oai/request"},"display":{"title":"Neuropathological significance of PLD1 in Alzheimer's disease and behavioral variant frontotemporal dementia","abstract":"Aberrantly elevated levels of Phospholipase D (PLD) activity is well documented in neurodysfunctional disorders including Alzheimer’s disease (AD). Our lab established, for the first time, an elevated PLD1 expression in crude synaptosomes from AD post-mortem brains and further demonstrated the effect of amyloidogenic insults amyloid-β (Aβ) and tau in wildtype mice, implicating a role for PLD1 in synaptic deficits. Given this background, I implemented a 12-month-old 3xTg-AD mouse model; to corroborate a pathological role for PLD1 in AD where neuropathological hallmarks such as the Aβ and tau are well established. Attenuating PLD1 with a small molecule abrogated synaptotoxicity and thereby rescued cognitive deficits in the 12-month-old 3xTg-AD mice. I utilized human hippocampi from post-mortem brains of AD patients and a 12-month-old 3xTg mouse model to substantiate the association of PLD1 with the amyloidogenic insults. In addition, I reported the effect of attenuating PLD1 in promoting synaptic resilience using behavioral paradigm and electrophysiology. Considering the beneficial effects of PLD1 attenuation in the 3xTg-AD late-onset AD mouse model with pronounced tau effects, I addressed the premise of PLD1 signalosome in the etiology of a primary tauopathy, bvFTD (behavioral variant Frontotemporal Dementia or Pick’s disease). To establish the scientific premise, I used postmortem brain regions donated by the patients to NeuroBioBank under MTA (material transfer agreement) to demonstrate a neuropathological significance of PLD1 in tau-driven dementia. I performed immunofluorescence, and Western blot analyses, fluorescence assisted single synaptosome-long term potentiation (FASS-LTP) assay to understand the PLD1-associated insults in bvFTD. I found that PLD1 co-localizes with hyperphosphorylated tau, a classical hallmark of bvFTD. Interestingly, this co-localization significantly correlated with the association of PLD1 with total tau or non-phosphorylated tau implying a significant role for PLD1 in the pathology of Pick’s disease. Additionally, I found that bvFTD patients exhibited reduction in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits; GluA3 and A4, that may contribute to the observed deficits in FASS-LTP. This dissertation provides its readers with valuable insights into the neuropathological significance of PLD1 in synaptic degeneration and its implications on cognitive decline in AD and bvFTD.","abstract_html":"Aberrantly elevated levels of Phospholipase D (PLD) activity is well documented in neurodysfunctional disorders including Alzheimer’s disease (AD). Our lab established, for the first time, an elevated PLD1 expression in crude synaptosomes from AD post-mortem brains and further demonstrated the effect of amyloidogenic insults amyloid-β (Aβ) and tau in wildtype mice, implicating a role for PLD1 in synaptic deficits. Given this background, I implemented a 12-month-old 3xTg-AD mouse model; to corroborate a pathological role for PLD1 in AD where neuropathological hallmarks such as the Aβ and tau are well established. Attenuating PLD1 with a small molecule abrogated synaptotoxicity and thereby rescued cognitive deficits in the 12-month-old 3xTg-AD mice. I utilized human hippocampi from post-mortem brains of AD patients and a 12-month-old 3xTg mouse model to substantiate the association of PLD1 with the amyloidogenic insults. In addition, I reported the effect of attenuating PLD1 in promoting synaptic resilience using behavioral paradigm and electrophysiology. Considering the beneficial effects of PLD1 attenuation in the 3xTg-AD late-onset AD mouse model with pronounced tau effects, I addressed the premise of PLD1 signalosome in the etiology of a primary tauopathy, bvFTD (behavioral variant Frontotemporal Dementia or Pick’s disease). To establish the scientific premise, I used postmortem brain regions donated by the patients to NeuroBioBank under MTA (material transfer agreement) to demonstrate a neuropathological significance of PLD1 in tau-driven dementia. I performed immunofluorescence, and Western blot analyses, fluorescence assisted single synaptosome-long term potentiation (FASS-LTP) assay to understand the PLD1-associated insults in bvFTD. I found that PLD1 co-localizes with hyperphosphorylated tau, a classical hallmark of bvFTD. Interestingly, this co-localization significantly correlated with the association of PLD1 with total tau or non-phosphorylated tau implying a significant role for PLD1 in the pathology of Pick’s disease. Additionally, I found that bvFTD patients exhibited reduction in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits; GluA3 and A4, that may contribute to the observed deficits in FASS-LTP. This dissertation provides its readers with valuable insights into the neuropathological significance of PLD1 in synaptic degeneration and its implications on cognitive decline in AD and bvFTD.","abstract_has_math":false,"creators":["Natarajan, Chandramouli 1985-"],"institution":"The University of Texas Medical Branch at Galveston","degree_name":"Neuroscience (Doctoral)","degree_level":null,"degree_discipline":"Neuroscience","degree_department":null,"school":null,"contributors":[],"advisors":["Krishnan, Balaji (bakrishn@utmb.edu)"],"committee_chairs":[],"committee_members":["Dr. Giulio Taglialatela, gtaglial@utmb.edu","Dr. Rakez Kayed, rakayed@utmb.edu","Dr.Agenor Limon aglimonr@utmb.edu","Dr.Michael R. Nichols, nicolsmic@umsl.edu"],"year":2024,"date_issued":"2024-05","date_published":"2024-05","updated_at":"2026-07-24T05:50:54Z","subjects":[],"languages":["English"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2152.3/12670","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Krishnan, Balaji (bakrishn@utmb.edu)"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Dr. Giulio Taglialatela, gtaglial@utmb.edu","Dr. Rakez Kayed, rakayed@utmb.edu","Dr.Agenor Limon aglimonr@utmb.edu","Dr.Michael R. 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Our lab established, for the first time, an elevated PLD1 expression in crude synaptosomes from AD post-mortem brains and further demonstrated the effect of amyloidogenic insults amyloid-β (Aβ) and tau in wildtype mice, implicating a role for PLD1 in synaptic deficits. Given this background, I implemented a 12-month-old 3xTg-AD mouse model; to corroborate a pathological role for PLD1 in AD where neuropathological hallmarks such as the Aβ and tau are well established. Attenuating PLD1 with a small molecule abrogated synaptotoxicity and thereby rescued cognitive deficits in the 12-month-old 3xTg-AD mice. I utilized human hippocampi from post-mortem brains of AD patients and a 12-month-old 3xTg mouse model to substantiate the association of PLD1 with the amyloidogenic insults. In addition, I reported the effect of attenuating PLD1 in promoting synaptic resilience using behavioral paradigm and electrophysiology. Considering the beneficial effects of PLD1 attenuation in the 3xTg-AD late-onset AD mouse model with pronounced tau effects, I addressed the premise of PLD1 signalosome in the etiology of a primary tauopathy, bvFTD (behavioral variant Frontotemporal Dementia or Pick’s disease). To establish the scientific premise, I used postmortem brain regions donated by the patients to NeuroBioBank under MTA (material transfer agreement) to demonstrate a neuropathological significance of PLD1 in tau-driven dementia. I performed immunofluorescence, and Western blot analyses, fluorescence assisted single synaptosome-long term potentiation (FASS-LTP) assay to understand the PLD1-associated insults in bvFTD. I found that PLD1 co-localizes with hyperphosphorylated tau, a classical hallmark of bvFTD. Interestingly, this co-localization significantly correlated with the association of PLD1 with total tau or non-phosphorylated tau implying a significant role for PLD1 in the pathology of Pick’s disease. Additionally, I found that bvFTD patients exhibited reduction in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits; GluA3 and A4, that may contribute to the observed deficits in FASS-LTP. This dissertation provides its readers with valuable insights into the neuropathological significance of PLD1 in synaptic degeneration and its implications on cognitive decline in AD and bvFTD."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Neuropathological significance of PLD1 in Alzheimer's disease and behavioral variant frontotemporal dementia"]}]}],"canonical_facts":{"dc:contributor.advisor":["Krishnan, Balaji (bakrishn@utmb.edu)"],"dc:contributor.committeemember":["Dr. Giulio Taglialatela, gtaglial@utmb.edu","Dr. Rakez Kayed, rakayed@utmb.edu","Dr.Agenor Limon aglimonr@utmb.edu","Dr.Michael R. Nichols, nicolsmic@umsl.edu"],"dc:creator":["Natarajan, Chandramouli 1985-"],"dc:date.accessioned":["2025-04-08T12:46:49Z"],"dc:date.available":["2025-04-08T12:46:49Z"],"dc:date.issued":["2024-05"],"dc:description.abstract":["Aberrantly elevated levels of Phospholipase D (PLD) activity is well documented in neurodysfunctional disorders including Alzheimer’s disease (AD). Our lab established, for the first time, an elevated PLD1 expression in crude synaptosomes from AD post-mortem brains and further demonstrated the effect of amyloidogenic insults amyloid-β (Aβ) and tau in wildtype mice, implicating a role for PLD1 in synaptic deficits. Given this background, I implemented a 12-month-old 3xTg-AD mouse model; to corroborate a pathological role for PLD1 in AD where neuropathological hallmarks such as the Aβ and tau are well established. Attenuating PLD1 with a small molecule abrogated synaptotoxicity and thereby rescued cognitive deficits in the 12-month-old 3xTg-AD mice. I utilized human hippocampi from post-mortem brains of AD patients and a 12-month-old 3xTg mouse model to substantiate the association of PLD1 with the amyloidogenic insults. In addition, I reported the effect of attenuating PLD1 in promoting synaptic resilience using behavioral paradigm and electrophysiology. Considering the beneficial effects of PLD1 attenuation in the 3xTg-AD late-onset AD mouse model with pronounced tau effects, I addressed the premise of PLD1 signalosome in the etiology of a primary tauopathy, bvFTD (behavioral variant Frontotemporal Dementia or Pick’s disease). To establish the scientific premise, I used postmortem brain regions donated by the patients to NeuroBioBank under MTA (material transfer agreement) to demonstrate a neuropathological significance of PLD1 in tau-driven dementia. I performed immunofluorescence, and Western blot analyses, fluorescence assisted single synaptosome-long term potentiation (FASS-LTP) assay to understand the PLD1-associated insults in bvFTD. I found that PLD1 co-localizes with hyperphosphorylated tau, a classical hallmark of bvFTD. Interestingly, this co-localization significantly correlated with the association of PLD1 with total tau or non-phosphorylated tau implying a significant role for PLD1 in the pathology of Pick’s disease. Additionally, I found that bvFTD patients exhibited reduction in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits; GluA3 and A4, that may contribute to the observed deficits in FASS-LTP. This dissertation provides its readers with valuable insights into the neuropathological significance of PLD1 in synaptic degeneration and its implications on cognitive decline in AD and bvFTD."],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://hdl.handle.net/2152.3/12670"],"dc:language.iso":["English"],"dc:title":["Neuropathological significance of PLD1 in Alzheimer's disease and behavioral variant frontotemporal dementia"],"dc:type":["Thesis"],"thesis:degree_discipline":["Neuroscience"],"thesis:degree_name":["Neuroscience (Doctoral)"],"thesis:institution_name":["The University of Texas Medical Branch at Galveston"]},"updated_at":"2026-07-24T05:50:54Z"}