Of particular note, while there were dramatic decreases in cerebellar white matter PlsEtns, there were no changes in cerebellar gray matter PlsEtns even in late stage AD [9]. PlsEtn changes were also shown to be specific in that phosphatidylethanolamines, serine glycerophospholipids and inositol glycerophospholipids were unaltered [8-10] (nomenclature and structures are presented in Figure ?Figure11). Vorinostat MK0683 Figure 1 Chemical structures of glycerophospholipids. Phosphatidyl glycerophospholipids are diacyl lipids in which fatty acids are the substituents at sn-1 and sn-2 and charged bases (PEtn, PCh, PSer or PIn) at sn-3. Ether lipids possess a fatty alcohol at sn-1 … Figure 2 Inter-relationships of ethanolamine glycerophospholipid and sphingolipid pathways.

The boxed reactions are conducted in peroxisomes while the other reactions are mainly in the endoplasmic reticulum. Red lipids are decreased in Alzheimer’s disease brain … Subsequent research demonstrated disease severity-dependent decreases in circulating DHA and PlsEtns, particularly PlsEtns containing DHA at sn-2 [11,12]. While plasma DHA is derived both from the diet and from peroxisome-dependent synthesis by the liver and gastrointestinal epithelium, peroxisomes are obligatory for PlsEtn synthesis [13]. Based on these data, a peroxisomal deficit in AD was proposed [11] and was soon demonstrated in AD liver [14] and AD brain [15,16]; however, these data do not also preclude a contribution of lipid peroxidation in plasmalogen decrements or potential drug-induced liver toxicity.

Brain and liver DHA is decreased in AD tissues and pristanic acid, a metabolite of dietary phytanic acid that is metabolized exclusively by peroxisomes [17], is elevated in AD liver [14]. Decreases in AD brain PlsEtn levels are accompanied by accumulation of very long chain fatty acids (VLCFAs): behenic acid (C22:0), lignoceric acid (C24:0) and hexacosanoic Batimastat acid (C26:0) [15]. These VLCFAs are all metabolized by peroxisomes [13,15], again supporting peroxisomal dysfunction in AD. Furthermore, the decrements in brain [9], liver [14] and plasma [11,12] DHA-containing plasmalogens and the accumulation of VLCFAs in the cortex [15] correlate with cognitive deficit in AD patients. In contrast, decreases in white matter PlsEtns occur early in the disease process and do not correlate with cognitive status [9].

Supply of PlsEtn building blocks to the central nervous system (CNS) is complicated in that a number of lipid transport mechanisms are involved. DHA (omega-3) and arachidonic acid (omega-6), which are long chain polyunsaturated fatty acids essential make it clear for PlsEtn synthesis, comprise 8% and 6% of brain dry weight, respectively [1]. Fatty acid binding proteins [18] are major determinants of fatty acid transport into and within the CNS.