Introduction: Phospholipase D (PLD), a lipolytic enzyme that breaks down membrane phospholipids, is also involved in signaling mechanisms downstream of seven transmembrane receptors. Abnormally elevated levels of PLD activity are well-established in Alzheimer's disease (AD), implicating the two isoforms of mammalian phosphatidylcholine cleaving PLD (PC-PLD1 and PC-PLD2). Therefore, we took a systematic approach of investigating isoform-specific expression in human synaptosomes and further investigated the possibility of therapeutic intervention using preclinical studies.
Methods: Synaptosomal Western blot analyses on the postmortem human hippocampus, temporal cortex, and frontal cortex of AD patient brains/age-matched controls and the 3XTg-AD mice hippocampus (mouse model with overexpression of human amyloid precursor protein, presenilin-1 gene, and microtubule-associated protein tau causing neuropathology progressing comparable to that in human AD patients) were used to detect the levels of neuronal PLD1 expression. Mouse hippocampal long-term potentiation of PLD1-dependent changes was studied using pharmacological approaches in ex vivo slice preparations from wild-type and transgenic mouse models. Finally, PLD1-dependent changes in novel object recognition memory were assessed following PLD1 inhibition.
Results: We observed elevated synaptosomal PLD1 in the hippocampus/temporal cortex from postmortem tissues of AD patients compared to age-matched controls and age-dependent hippocampal PLD1 increases in 3XTg-AD mice. PLD1 inhibition blocked effects of oligomeric amyloid β or toxic oligomeric tau species on high-frequency stimulation long-term potentiation and novel object recognition deficits in wild-type mice. Finally, PLD1 inhibition blocked long-term potentiation deficits normally observed in aging 3XTg-AD mice.
Discussion: Using human studies, we propose a novel role for PLD1-dependent signaling as a critical mechanism underlying oligomer-driven synaptic dysfunction and consequent memory disruption in AD. We, further, provide the first set of preclinical studies toward future therapeutics targeting PLD1 in slowing down/stopping the progression of AD-related memory deficits as a complementary approach to immunoscavenging clinical trials that are currently in progress.
Keywords: Alzheimer's disease; Aβ; Electrophysiology; Hippocampus; Memory; Novel object recognition; Phospholipase D; Synaptic; Tau.