Suppressing aberrant phospholipase D1 signaling in 3xTg Alzheimer\u2019s disease mouse model promotes synaptic resilience

Krystyn Z Bourne,Chandramouli Natarajan,Giulio Taglialatela,Batbayar Tumurbaatar,Balaji Krishnan,Carlos X Medina Perez

doi:10.1038/s41598-019-54974-6

Krystyn Z Bourne, Chandramouli Natarajan + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-54974-6

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Abstract

Current approaches in treatment of Alzheimer’s disease (AD) is focused on early stages of cognitive decline. Identifying therapeutic targets that promote synaptic resilience during early stages may prevent progressive memory deficits by preserving memory mechanisms. We recently reported that the inducible isoform of phospholipase D (PLD1) was significantly increased in synaptosomes from post-mortem AD brains compared to age-matched controls. Using mouse models, we reported that the aberrantly elevated neuronal PLD1 is key for oligomeric amyloid driven synaptic dysfunction and underlying memory deficits. Here, we demonstrate that chronic inhibition using a well-tolerated PLD1 specific small molecule inhibitor is sufficient to prevent the progression of synaptic dysfunction during early stages in the 3xTg-AD mouse model. Firstly, we report prevention of cognitive decline in the inhibitor-treated group using novel object recognition (NOR) and fear conditioning (FC). Secondly, we provide electrophysiological assessment of better synaptic function in the inhibitor-treated group. Lastly, using Golgi staining, we report that preservation of dendritic spine integrity as one of the mechanisms underlying the action of the small molecule inhibitor. Collectively, these studies provide evidence for inhibition of PLD1 as a potential therapeutic strategy in preventing progression of cognitive decline associated with AD and related dementia.

Highlights

Alzheimer’s Disease (AD) is the most prevalent form of dementia and the sixth leading cause of death
Since VU01 administration does not affect wildtype behavior, we addressed the effects of VU01 in preventing synaptic dysfunction and the underlying memory deficits driven by progressive accumulation of oligomers of Aβ and tau in 6-month old 3xTg-Alzheimer’s disease (AD) mice using saline-injected age-matched 3xTg-AD siblings where PLD1 levels are elevated[18] as appropriate controls
While the hippocampal recovery was robustly observed in the PLD1 inhibitor injected mice (S: 59.720 ± 2.798 vs I: 77.670 ± 1.743; *p < 0.05; Mann-Whitney U; Fig. 2C); the cued responses failed to show a significant difference between the two groups (S: 84.040 ± 3.528 vs I: 91.870 ± 1.440; ns; Kruskal-Wallis one-way ANOVA; Fig. 2D)

Summary

Introduction

Alzheimer’s Disease (AD) is the most prevalent form of dementia and the sixth leading cause of death. The inducible PLD1 and constitutively expressed PLD2 isoforms share 53% homology and have redundant as well as isoform-specific effects on downstream targets Both membrane-associated enzymes conduct a transphosphatidylase activity by cleaving the most abundant membrane phospholipid, phosphatidyl choline (PC), into phosphatidic acid (PA) and choline. PLD1 levels are elevated following acute administration of toxic oligomers, and inhibition of PLD1 signaling in a pathological state was beneficial in preventing synaptic dysfunction and associated memory deficits[18]. Since VU01 administration does not affect wildtype behavior, we addressed the effects of VU01 in preventing synaptic dysfunction (electrophysiology) and the underlying memory deficits (behavior) driven by progressive accumulation of oligomers of Aβ (oAβ) and tau (otau) in 6-month old 3xTg-AD mice using saline-injected age-matched 3xTg-AD siblings where PLD1 levels are elevated[18] as appropriate controls. The preclinical outcomes reported here provide a clear evidence for the therapeutic potential of PLD1 inhibition in preventing progression of cognitive deficits in AD and related dementia

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