Lipid metabolism in Alzheimer’s disease

Abstract

Lipids play crucial roles in cell signaling and various physiological processes, especially in the brain. Impaired lipid metabolism in the brain has been implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), and other central nervous system insults. The brain contains thousands of lipid species, but the complex lipid compositional diversity and the function of each of lipid species are currently poorly understood. This review integrates current knowledge about major lipid changes with the molecular mechanisms that underlie AD pathogenesis. Keywords: brain aging; lipid metabolism; Alzheimer's disease ·Review· IntroductionLipids are abundant in the brain. These lipids consist of glycerophospholipids (GPs), sphingolipids, and cholesterol in roughly equimolar proportions [1] . The brain contains about 20% of the total body cholesterol [2] . Cholesterol is primarily derived from local synthesis, whereas uptake of lipoprotein particle-derived cholesterol from the peripheral circulation is usually prevented by the blood-brain-barrier. Lipids, especially cholesterol, have recently been extensively studied in many neurodegenerative diseases. Impairment of cholesterol metabolism (synthesis, transport, and utilization by neurons) in the brain is linked to Alzheimer's disease (AD) and the aging process. In addition, lipid oxidation products accumulate at high levels in aging tissues in mice [3] . Recent studies have demonstrated the important role of altered metabolism in AD [4] . Sphingomyelinases promote apoptosis in human primary neurons through the generation of a proapoptotic molecule, ceramide [5] .Moreover, upregulated arachidonic acid metabolism has been reported in hAPP-J20 AD mice as well as in the AD brain, particularly in regions having high densities of senile plaques with activated microglia [6,7] . Although the potential link between cholesterol and AD pathogenesis has been intensively studied, growing evidence suggests that other lipids, such as sphingolipids and GPs, also play an important role. Here, we review some recent advances in understanding the role lipids play in the aging process and AD pathogenesis. Major Lipid Classes and Functions in the BrainAlthough most lipids serve as structural lipids in cell membranes, they are also directly involved in membrane trafficking, intracellular architecture, and the regulation of proteins and sub-compartments in membranes (lipid rafts) (Table 1). Eukaryotic organisms might contain a dozen major lipid classes, each comprising hundreds of individual molecular species [8] . Lipids have the potential to generate 9 000-100 000 molecular species [9,10] , and a mammalian cell may contain 1 000-2 000 [11] . The brain is one of the most lipid-enriched organs, containing several major classes, such as cholesterol, GPs, sphingolipids and fatty acids [12] . The biological significance of the compositional complexity of lipids is poorly understood. However, the recent development of the shot-gun lipidomics technique may provide more sensitive and quant...

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