Phospholipase D in brain function and Alzheimer's disease

Abstract

Alzheimer's disease is the most common neurodegenerative disorder. Although lipids are major constituents of brain, their role in Alzheimer's disease pathogenesis is poorly understood. Much attention has been given to cholesterol, but growing evidence suggests that other lipids, such as phospholipids, might play an important role in this disorder. In this review, we will summarize the evidence linking phospholipase D, a phosphatidic acid-synthesizing enzyme, to multiple aspects of normal brain function and to Alzheimer's disease. The role of phospholipase D in signaling mechanisms downstream of beta-amyloid as well as in the trafficking and processing of amyloid precursor protein will be emphasized.

Figure 1

PLD structure, PA metabolism and reactions catalyzed by PLD. (a) Structure of PLD isozymes. Structurally, the two isozymes differ by the presence of a loop domain in the PLD1 isozyme. (b) PA metabolism. Besides the PLD source, PA can be generated from other sources and further metabolized as represented in the figure. The dashed arrow represents the biosynthetic pathway. The enzymes catalyzing the respective reactions are shown in red. (c) PLD activity. In the presence of water, PLD produces PA. In the presence of primary alcohols, such as ethanol, PLD has a 1000-fold higher affinity for primary alcohols as nucleophiles, leading to a preferential generation of phosphatidylethanol (PEtOH). PLD, Phospholipase D; PC, phosphatydilcholine; PA, phosphatidic acid; LPA, lyso-PA; DAG, diacylglycerol; CDP-DAG, cytidine diphosphate-DAG; PLA2, phospholipase A2; LPAAT, LPA acyltransferase; PAP, PA phosphatase; DGK, DAG kinase; CDS, CDP-DAG synthase; mitoPLD, mito-phospholipase D.