However, GPC phosphodiesterase Seliciclib (EC 3.1.4.2, EC 3.1.4.46), another enzyme that metabolizes GPC, is increased in AD cortex but not cerebellum [31]. In a non-targeted metabolomics study of AD plasma, decrements in LPC 16:0 (palmitic acid) and LPC 18:2 (linoleic acid) have been reported [32]. The anatomical source(s) of these circulating metabolites remains to be defined. In summary, it appears that peroxisomal deficits in AD [14-16] result in decreases in brain PlsChs and alterations in the metabolism of GPCs. The impact of alterations in the metabolism of GPCs on cholinergic neurotransmission remain to be investigated. These early autopsy studies need to be repeated and the individual PlsChs characterized, while studies of plasma LPCs require larger population-based studies.

Glycerophospholipid remodeling While brain glycerophospholipids possess almost exclusively palmitic (16:0), stearic (18:0) or oleic acid (18:1) at sn-1, the fatty acid substitution at sn-2 is much more varied. In white matter, the sn-2 position is dominated by oleic acid while in gray matter DHA (22:6) and arachidonic acid (20:4) predominate. A further critically important feature of the sn-2 fatty acid substitutions is that they are dynamic, undergoing continuous remodeling. Lipid remodeling is a process involved in the generation of a large family of PlsEtns and PlsChs in the brain. The lipid remodeling pathway involves removal of sn-2 fatty acids by the 2-acyl hydrolases, phospholipase A2 (EC 3.1.1.4) and acylglycerol lipase (EC 3.1.1.23) and reacylation, with alternative fatty acids, by acyl-CoA:lysophospholipid 2-acyltransferases [33].

Of the 22 different phospholipase A2 (PLA2) enzymes, several have been evaluated in AD. Plasmalogen-selective PLA2 [34] and cytosolic PLA2 [35] have been reported to be increased in AD cortex. Ca++-dependent PLA2 is increased in AD CSF [36], decreased in AD cortex [31], and unaffected in AD cerebellum [31]. Ca++-independent PLA2 is decreased in both AD CSF [37] and AD cortex [31], and unaffected in AD cerebellum [31]. Clearly, further characterization of changes in the multiple isoforms of PLA2 in AD is required. In parallel with increases in AD cortical plasmalogen-selective PLA2 [34], lysophospholipid acyltransferase is increased [31], further supporting the tight coupling of deacylation-reacylation in lipid remodeling.

This coordinated deacylation-reacylation mechanism appears to be located mainly in the endoplasmic reticulum [33], also the location of the final steps of plasmalogen and sphingolipid synthesis (Figure ?(Figure22). A major aspect of lipid remodeling that remains to be evaluated in AD are the signaling cascades AV-951 potentially evoked by lipids released by deacylation at sn-2 of glycerophospholipids. selleck chemical In the case of released arachidonic acid, a vast array of eicosanoids can be generated as mediators of neuroinflammation, a common feature of AD brain [38].