Neuropathological significance of PLD1 in Alzheimer's disease and behavioral variant frontotemporal dementia

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.

Name thesis:degree_name

Neuroscience (Doctoral)

Discipline thesis:degree_discipline

Neuroscience

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2024

Author dc:creator

• Natarajan, Chandramouli 1985-

Advisor dc:contributor.advisor

• Krishnan, Balaji (bakrishn@utmb.edu)

Committee members 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

Language dc:language.iso

English

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12670

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12670