Phospholipase D1 Attenuation Therapeutics Promotes Resilience against Synaptotoxicity in 12-Month-Old 3xTg-AD Mouse Model of Progressive Neurodegeneration

Chandramouli Natarajan, Charles Cook, Karthik Ramaswamy, Balaji Krishnan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Abrogating synaptotoxicity in age-related neurodegenerative disorders is an extremely promising area of research with significant neurotherapeutic implications in tauopathies including Alzheimer’s disease (AD). Our studies using human clinical samples and mouse models demonstrated that aberrantly elevated phospholipase D1 (PLD1) is associated with amyloid beta (Aβ) and tau-driven synaptic dysfunction and underlying memory deficits. While knocking out the lipolytic PLD1 gene is not detrimental to survival across species, elevated expression is implicated in cancer, cardiovascular conditions and neuropathologies, leading to the successful development of well-tolerated mammalian PLD isoform-specific small molecule inhibitors. Here, we address the importance of PLD1 attenuation, achieved using repeated 1 mg/kg of VU0155069 (VU01) intraperitoneally every alternate day for a month in 3xTg-AD mice beginning only from ~11 months of age (with greater influence of tau-driven insults) compared to age-matched vehicle (0.9% saline)-injected siblings. A multimodal approach involving behavior, electrophysiology and biochemistry corroborate the impact of this pre-clinical therapeutic intervention. VU01 proved efficacious in preventing in later stage AD-like cognitive decline affecting perirhinal cortex-, hippocampal- and amygdala-dependent behaviors. Glutamate-dependent HFS-LTP and LFS-LTD improved. Dendritic spine morphology showed the preservation of mushroom and filamentous spine characteristics. Differential PLD1 immunofluorescence and co-localization with Aβ were noted.

Original languageEnglish (US)
Article number3372
JournalInternational journal of molecular sciences
Volume24
Issue number4
DOIs
StatePublished - Feb 2023
Externally publishedYes

Keywords

  • Alzheimer’s disease
  • cognitive deficit
  • dyslipidemia
  • excitability
  • neurodegeneration
  • phospholipase D
  • synaptic homeostasis

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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