Assessing therapeutic potential of PLD1 inhibition in dementia: Systematic assessment of behavior, electrophysiology & mechanisms of synaptic dysfunction using different parameters including sex‐specific differences

Abstract

AbstractBackgroundPhosphatidyl choline phospholipase D (PC‐PLD), a lipolytic enzyme that breaks down membrane phospholipids via two isoforms ‐ a constitutively expressed PLD2 and an inducible PLD1 isoform ‐ are also involved in developmentally important signaling mechanisms that regulate synaptic function. We were the first to propose and present a systematic study that established PLD1 as the aberrantly elevated isoform in AD and related dementia using human clinical samples and provided functional proof using mouse models to demonstrate the underlying synaptic dysfunction and memory deficits.MethodsWe used different transgenic rodent models of AD‐like pathology and did a corroborative assessment of behavior, electrophysiology and biochemistry including western blots analysis, Golgi studies and immunofluorescence to assess the efficacy of treatment of the aberrantly elevated PLD1 levels using chronic regimen of a specific small molecule inhibitor.ResultChronic PLD1 inhibition is effective in ameliorating the synaptic dysfunction and associated memory deficits in the treated cohort compared to the age‐matched cohort. We also assessed and report sex‐specific changes in these responses that strengthen our understanding of the underlying mechanisms and brain regions that are targeted by the therapeutic approaches.ConclusionUsing chronic administration of a well‐tolerated halopemide derivative of the specific PLD1 isoform inhibitor in the preclinical mouse models of synaptic dysfunction and memory deficits associated with amyloidogenic effects of Aβ and tau, we demonstrated neuroprotective aspects involving changes in the dendritic spine integrity that contributes to the preservation of memory with an emphasis on the sex‐specific effects.