Phospholipase D2 Ablation Ameliorates Alzheimer's Disease-Linked Synaptic Dysfunction and Cognitive Deficits

Abstract

Growing evidence implicates aberrant lipid signaling in Alzheimer's disease (AD). While phospholipases A2 and C have been recentlyshown to mediate key actions of amyloid ␤-peptide (A␤) through a dysregulation of arachidonic acid and phosphatidylinositol-4,5-bisphosphate metabolism, respectively, the role of phospholipase D (PLD) has so far remained elusive. PLD produces phosphatidic acid (PA), a bioactive lipid involved in multiple aspects of cell physiology, including signaling and membrane trafficking processes. Here we show that oligomeric A␤ enhances PLD activity in cultured neurons and that this stimulatory effect does not occur upon ablation of PLD2 via gene targeting. A␤ fails to suppress long-term potentiation in PLD2-deficient hippocampal slices, suggesting that PLD2 is required for the synaptotoxic action of this peptide. In vivo PLD activity, as assessed by detection of phosphatidylethanol levels using mass spectrometry (MS) following ethanol injection, is also increased in the brain of a transgenic mouse model of AD (SwAPP). Furthermore, Pld2 ablation rescues memory deficits and confers synaptic protection in SwAPP mice despite a significant A␤ load. MS-based lipid analysis of Pld2 mutant brains in the presence or absence of the SwAPP transgene unmasks striking crosstalks between different PA species. This lipid analysis shows an exquisite acyl chain specificity and plasticity in the perturbation of PA metabolism. Collectively, our results point to specific molecular species of PA as key modulators of AD pathogenesis and identify PLD2 as a novel potential target for therapeutics.

Comparative Lipidomic Analysis of Mouse and Human Brain with Alzheimer Disease

“…32:1 and 34:2) was also observed. These data are in contrast to the specific increase of PA 34:2 seen in a different strain of Swedish APP transgenic mice that were also older in age (11). To determine whether this was an age-related phenomenon, we conducted a targeted PA analysis of 14 -15-month-old APP mice of the same genetic background and found that PA 34:2, and to a lower extent other molecular species of PA, were indeed elevated in these mice relative to 9 -11-month-old APP mice (supplemental Fig.…”

“…For instance, ␥-secretase activity is regulated by membrane levels of cholesterol and sphingomyelin (SM) (8). Second, A␤ exerts its cytotoxic effects primarily by perturbing cellular membranes, in part by modulating the activity of phospholipases, such as PLA 2 (9), PLC (10), and phospholipase D 2 (PLD 2 ) (11). Third, lipids, such as ganglioside GM1, modulate the pathogenic potential of A␤ by affecting its propensity to aggregate (12).…”

“…Several studies focusing on defined families of lipids have made use of this technology to analyze lipid composition from AD brain tissue, showing changes in plasmalogen phosphatidylethanolamine (pPE) (14), sulfatide (Sulf) (15), ceramide (Cer), galactosylceramide (GalCer), cholesterol (16), and alkylacylglycerophosphocholine (17). Our own study has shown that a specific molecular species of phosphatidic acid (PA) previously linked to neurodegeneration in the fly (18) accumulates in the forebrain of old Swedish APP (swAPP) mice (11).…”

Phospholipase D1 regulates autophagic flux and clearance of α-synuclein aggregates

“…However, a recent study showed that genetic ablation of PLD2 ameliorated synaptic dysfunction and cognitive decline in models of AD. 38 Therefore, understanding isotype-specific effects of PLD would be necessary for identifying effective therapeutic strategies targeting PLD enzymes.…”

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

“…Finally, many studies identified intracellular mediators of the A␤ peptide neurotoxic effects. These intracellular targets include membrane-phospholipid remodeling enzymes such as synaptojanin and phospholipase D (Berman et al, 2008;Oliveira et al, 2010) or signaling proteins such as fyn kinase, glycogen synthase kinase-3␤, cyclin-dependent kinase-5 (Crews and Masliah, 2010). Some inhibitors of these putative therapeutic targets have been proposed because of their potential specificity.…”