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

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.

Phospholipase D, a Novel Therapeutic Target Contributes to the Pathogenesis of Neurodegenerative and Neuroimmune Diseases

“…Interestingly, PLD1 physically interacts and colocalizes with amyloid precursor protein (APP) and caveolin-3 [ 49 ]. One study discovered that APP correlates with the structural pleckstrin domain of PLD1 homolog, and that the amyloid region of APP interacts with PLD, suggesting that the upregulation of PLD1 may play a role in AD associated neuronal pathology [ 50 ]. Bourne et al [ 51 ] reported that an abnormal increase in neuronal PLD1 is crucial for oligomeric amyloid formation, which can lead to synaptic dysfunction and potential memory deficits.…”

“…The PLD3 level in human prefrontal cortex was found to be inversely associated with the severity of A β pathology as well as the rate of cognitive decline in 531 participants enrolled in the aging project [ 55 ]. Accumulation of A β in the brain mediates various aspects of the pathogenesis of attention deficit disorder, and A β -stimulated PLD activity correlates with lactate dehydrogenase release, an indicator of cell death, suggesting that the neurotoxic effects of amyloid are mediated by PLD [ 50 ]. PLD1/2 is also involved in APP and presenilin trafficking and it is crucial for APP metabolism and secretion [ 56 ].…”