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Linking lipids to Alzheimer's disease: cholesterol and beyond

An Erratum to this article was published on 23 June 2011

This article has been updated

Key Points

  • Dysregulation of lipid pathways has been implicated in a growing number of neurodegenerative disorders, including Alzheimer's disease.

  • Lipids control many aspects that are relevant for Alzheimer's disease pathogenesis: these include the trafficking and processing of amyloid precursor protein, the synaptotoxic signalling of amyloid-β and tau pathology.

  • Although the link between cholesterol metabolism and Alzheimer's disease pathogenesis is well-established, recent studies suggest that other lipid families, such as phospholipids, play a key part in Alzheimer's disease-linked synaptic dysfunction.

  • As regulators of lipid metabolism, such as statins, are successful classes of marketed drugs, identification of novel regulators of lipid pathways involved in Alzheimer's disease pathogenesis may offer new avenues for the treatment of this devastating disorder.

  • Mass spectrometry-based techniques are powerful tools to analyse the 'lipidome' of brain regions affected by Alzheimer's disease, either in humans or in genetic models. These approaches can uncover lipid pathways that are dysregulated in Alzheimer's disease, as well as novel biomarkers for this disorder.

Abstract

Lipid-mediated signalling regulates a plethora of physiological processes, including crucial aspects of brain function. In addition, dysregulation of lipid pathways has been implicated in a growing number of neurodegenerative disorders, such as Alzheimer's disease (AD). Although much attention has been given to the link between cholesterol and AD pathogenesis, growing evidence suggests that other lipids, such as phosphoinositides and phosphatidic acid, have an important role. Regulators of lipid metabolism (for example, statins) are a highly successful class of marketed drugs, and exploration of lipid dysregulation in AD and identification of novel therapeutic agents acting through relevant lipid pathways offers new and effective options for the treatment of this devastating disorder.

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Figure 1: Contribution of cholesterol and apolipoprotein E metabolism to biogenesis, degradation and assembly of amyloid-β peptide.
Figure 2: Modulation of proteolytic processing of amyloid precursor protein (APP) by lipids.
Figure 3: Role of lipids in Amyloid-β-induced alterations in neuronal signalling and synaptic plasticity.

Change history

  • 01 April 2011

    Fig 2 and Fig 3 have been corrected on both html and pdf versions.

  • 23 June 2011

    On page 284 of this article, in the author addresses section, the e-mail address for Gilbert Di Paolo was incorrect. The correct e-mail address is: gil.dipaolo@columbia.edu

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Acknowledgements

We would like to thank R. Chan, T. G. Oliveira, D. Berman and L. B. McIntire for critical reading of the manuscript. Work from the authors is supported by US National Institutes of Health grants NS056049, HD05547 and AG033212 (G.D.P.), and NS074536 and AG033199 (T.-W.K.), the American Health Assistance Foundation (T.-W.K.), the Cure Alzheimer's Fund (T.-W.K.), the Alzheimer's Drug Discovery Foundation (T.-W.K.), the Alzheimer's Association (G.D.P.) and the McKnight Foundation (G.D.P.).

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The mevalonate pathway and cholesterol metabolism. (PDF 965 kb)

Supplementary information S2

Sphingolipids and glycosphingiolipids. (PDF 1981 kb)

Supplementary information S3

Glycerophospholipids and fatty acids. (PDF 1036 kb)

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Di Paolo, G., Kim, TW. Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat Rev Neurosci 12, 284–296 (2011). https://doi.org/10.1038/nrn3012

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