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. 2012 Feb 1;4(1):5.
doi: 10.1186/alzrt103.

Lipidomics of Alzheimer's disease: current status

Paul L Wood  1
Affiliations

Lipidomics of Alzheimer's disease: current status

Paul L Wood. Alzheimers Res Ther. .

Abstract

Alzheimer's disease (AD) is a cognitive disorder with a number of complex neuropathologies, including, but not limited to, neurofibrillary tangles, neuritic plaques, neuronal shrinkage, hypomyelination, neuroinflammation and cholinergic dysfunction. The role of underlying pathological processes in the evolution of the cholinergic deficit responsible for cognitive decline has not been elucidated. Furthermore, generation of testable hypotheses for defining points of pharmacological intervention in AD are complicated by the large scale occurrence of older individuals dying with no cognitive impairment despite having a high burden of AD pathology (plaques and tangles). To further complicate these research challenges, there is no animal model that reproduces the combined hallmark neuropathologies of AD. These research limitations have stimulated the application of 'omics' technologies in AD research with the goals of defining biologic markers of disease and disease progression and uncovering potential points of pharmacological intervention for the design of AD therapeutics. In the case of sporadic AD, the dominant form of dementia, genomics has revealed that the ε4 allele of apolipoprotein E, a lipid transport/chaperone protein, is a susceptibility factor. This seminal observation points to the importance of lipid dynamics as an area of investigation in AD. In this regard, lipidomics studies have demonstrated that there are major deficits in brain structural glycerophospholipids and sphingolipids, as well as alterations in metabolites of these complex structural lipids, which act as signaling molecules. Peroxisomal dysfunction appears to be a key component of the changes in glycerophospholipid deficits. In this review, lipid alterations and their potential roles in the pathophysiology of AD are discussed.

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Figures

Figure 1
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 and a fatty acid at sn-2. In plasmalogens, the fatty alcohol at sn-1 possesses a desaturation at the first two carbons in the fatty alcohol substitution. Loss of a fatty acid generates the lysophosphatidyl glycerophospholipids, via deacylation at sn-2 of diacyl glycerophospholipids.
Figure 2
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 while blue lipids are increased. The same color scheme is used for the tabular presentation of the various enzymes involved in glycerophospholipid and sphingolipid metabolism. CDP-ethanolamine from sphingolipid metabolism could provide the charged base for synthesis of ethanolamine plasmalogens. CDP, cytidine-diphosphate; CDP-E, cytidine-diphosphate ethanolamine; DHAP, dihydroxyacetone phosphate; GP, glycerolphosphate; GPC, glycerophosphocholine; GPE, glycerophosphoethanolamine; PE, phosphoethanolamine; S-1-P, sphingosine-1-phosphate; Sa-1-P, sphinganine-1-P.
Figure 3
Figure 3
Chemical structures of the amino alcohol precursors and their sphingolipid products. MW, molecular weight.
See this image and copyright information in PMC

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