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.
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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Chemical chaperones ameliorate neurodegenerative disorders in Derlin-1-deficient mice via improvement of cholesterol biosynthesis
Scientific Reports Open Access 17 December 2022
Dyslipidemia induced large-scale network connectivity abnormality facilitates cognitive decline in the Alzheimer’s disease
Journal of Translational Medicine Open Access 06 December 2022
Alzheimer's Research & Therapy Open Access 03 November 2022
Subscribe to Journal
Get full journal access for 1 year
only $6.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Haass, C. & Selkoe, D. J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nature Rev. Mol. Cell Biol. 8, 101–112 (2007).
Tanzi, R. E. & Bertram, L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120, 545–555 (2005).
Ballatore, C., Lee, V. M. & Trojanowski, J. Q. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nature Rev. Neurosci. 8, 663–672 (2007).
Small, S. A. & Duff, K. Linking Aβ and tau in late-onset Alzheimer's disease: a dual pathway hypothesis. Neuron 60, 534–542 (2008).
Foley, P. Lipids in Alzheimer's disease: a century-old story. Biochim. Biophys. Acta 1801, 750–753 (2010). This is an interesting historical perspective highlighting how 'lipoid bodies' and more generally, lipid defects, were originally described by Alois Alzheimer and his colleagues at the beginning of the twentieth century.
Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).
Bertram, L. & Tanzi, R. E. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nature Rev. Neurosci. 9, 768–778 (2008).
Bu, G. Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nature Rev. Neurosci. 10, 333–344 (2009).
Kim, J., Basak, J. M. & Holtzman, D. M. The role of apolipoprotein E in Alzheimer's disease. Neuron 63, 287–303 (2009).
Hartmann, T., Kuchenbecker, J. & Grimm, M. O. Alzheimer's disease: the lipid connection. J. Neurochem. 103, 159–170 (2007).
Dietschy, J. M. & Turley, S. D. Cholesterol metabolism in the brain. Curr. Opin. Lipidol. 12, 105–112 (2001).
Mesmin, B. & Maxfield, F. R. Intracellular sterol dynamics. Biochim. Biophys. Acta 1791, 636–645 (2009).
Vance, J. E., Hayashi, H. & Karten, B. Cholesterol homeostasis in neurons and glial cells. Semin. Cell Dev. Biol. 16, 193–212 (2005).
Chang, T. Y., Chang, C. C., Ohgami, N. & Yamauchi, Y. Cholesterol sensing, trafficking, and esterification. Annu. Rev. Cell Dev. Biol. 22, 129–157 (2006).
Puglielli, L. et al. Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide. Nature Cell Biol. 3, 905–912 (2001).
Bhattacharyya, R. & Kovacs, D. M. ACAT inhibition and amyloid β reduction. Biochim. Biophys. Acta 1801, 960–965 (2010).
Hutter-Paier, B. et al. The ACAT inhibitor CP-113,818 markedly reduces amyloid pathology in a mouse model of Alzheimer's disease. Neuron 44, 227–238 (2004). This study provides the first in vivo pharmacological evidence demonstrating that inhibition of ACAT reduces the amyloid burden in the brain of a mouse model of Alzheimer's disease.
Bryleva, E. Y. et al. ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. Proc. Natl Acad. Sci. USA 107, 3081–3086 (2010). This is a study that genetically validates the functional connection between ACAT and amyloid-β pathology in a mouse model.
Hirsch-Reinshagen, V., Burgess, B. L. & Wellington, C. L. Why lipids are important for Alzheimer disease? Mol. Cell. Biochem. 326, 121–129 (2009).
Tall, A. R. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J. Intern. Med. 263, 256–273 (2008).
Sun, Y., Yao, J., Kim, T. W. & Tall, A. R. Expression of liver X receptor target genes decreases cellular amyloid β peptide secretion. J. Biol. Chem. 278, 27688–27694 (2003).
Hirsch-Reinshagen, V. et al. The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J. Biol. Chem. 280, 43243–43256 (2005).
Koldamova, R., Staufenbiel, M. & Lefterov, I. Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J. Biol. Chem. 280, 43224–43235 (2005).
Wahrle, S. E. et al. Deletion of Abca1 increases Aβ deposition in the PDAPP transgenic mouse model of Alzheimer disease. J. Biol. Chem. 280, 43236–43242 (2005).
Simons, M. et al. Cholesterol depletion inhibits the generation of β-amyloid in hippocampal neurons. Proc. Natl Acad. Sci. USA 95, 6460–6464 (1998). This is an original paper highlighting the role of cholesterol in the metabolism of APP.
Vetrivel, K. S. & Thinakaran, G. Membrane rafts in Alzheimer's disease β-amyloid production. Biochim. Biophys. Acta 1801, 860–867 (2010).
Kalvodova, L. et al. Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro. J. Biol. Chem. 280, 36815–36823 (2005). References 27, 30 and 31 collectively demonstrate the impact of lipid composition on the catalytic activity of both BACE1 and γ-secretase.
Fassbender, K. et al. Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo. Proc. Natl Acad. Sci. USA 98, 5856–5861 (2001).
Wahrle, S. et al. Cholesterol-dependent γ-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol. Dis. 9, 11–23 (2002).
Osenkowski, P., Ye, W., Wang, R., Wolfe, M. S. & Selkoe, D. J. Direct and potent regulation of γ-secretase by its lipid microenvironment. J. Biol. Chem. 283, 22529–22540 (2008).
Osawa, S. et al. Phosphoinositides suppress γ-secretase in both the detergent-soluble and -insoluble states. J. Biol. Chem. 283, 19283–19292 (2008).
Riddell, D. R., Christie, G., Hussain, I. & Dingwall, C. Compartmentalization of β-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Curr. Biol. 11, 1288–1293 (2001).
Ehehalt, R., Keller, P., Haass, C., Thiele, C. & Simons, K. Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts. J. Cell Biol. 160, 113–123 (2003).
Vetrivel, K. S. et al. Alzheimer disease Aβ production in the absence of S-palmitoylation-dependent targeting of BACE1 to lipid rafts. J. Biol. Chem. 284, 3793–3803 (2009).
Benjannet, S. et al. Post-translational processing of β-secretase (β-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-β production. J. Biol. Chem. 276, 10879–10887 (2001).
Hattori, C. et al. BACE1 interacts with lipid raft proteins. J. Neurosci. Res. 84, 912–917 (2006).
Marquer, C. et al. Local cholesterol increase triggers amyloid precursor protein-Bace1 clustering in lipid rafts and rapid endocytosis. FASEB J. 21 Jan 2011 (doi:10.1096/fj.10-168633).
Yoon, I. S. et al. Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway. FASEB J. 21, 2742–2752 (2007).
Schneider, A. et al. Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons. J. Neurosci. 28, 2874–2882 (2008).
Urano, Y. et al. Association of active γ-secretase complex with lipid rafts. J. Lipid Res. 46, 904–912 (2005).
Vetrivel, K. S. et al. Spatial segregation of γ-secretase and substrates in distinct membrane domains. J. Biol. Chem. 280, 25892–25900 (2005).
Hannun, Y. A. & Obeid, L. M. Principles of bioactive lipid signalling: lessons from sphingolipids. Nature Rev. Mol. Cell Biol. 9, 139–150 (2008).
Posse de Chaves, E. & Sipione, S. Sphingolipids and gangliosides of the nervous system in membrane function and dysfunction. FEBS Lett. 584, 1748–1759 (2010).
He, X., Huang, Y., Li, B., Gong, C. X. & Schuchman, E. H. Deregulation of sphingolipid metabolism in Alzheimer's disease. Neurobiol. Aging 31, 398–408 (2008).
Puglielli, L., Ellis, B. C., Saunders, A. J. & Kovacs, D. M. Ceramide stabilizes β-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid β-peptide biogenesis. J. Biol. Chem. 278, 19777–19783 (2003).
Castro, B. M., Silva, L. C., Fedorov, A., de Almeida, R. F. & Prieto, M. Cholesterol-rich fluid membranes solubilize ceramide domains: implications for the structure and dynamics of mammalian intracellular and plasma membranes. J. Biol. Chem. 284, 22978–22987 (2009).
Grimm, M. O. et al. Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin. Nature Cell Biol. 7, 1118–1123 (2005). This study provides robust evidence in support of a link between APP, presenilin and the metabolism of sterols and sphingolipids.
Sawamura, N. et al. Modulation of amyloid precursor protein cleavage by cellular sphingolipids. J. Biol. Chem. 279, 11984–11991 (2004).
Fantini, J., Garmy, N., Mahfoud, R. & Yahi, N. Lipid rafts: structure, function and role in HIV, Alzheimer's and prion diseases. Expert Rev. Mol. Med. 4, 1–22 (2002).
Zhang, D., Manna, M., Wohland, T. & Kraut, R. Alternate raft pathways cooperate to mediate slow diffusion and efficient uptake of a sphingolipid tracer to degradative and recycling compartments. J. Cell Sci. 122, 3715–3728 (2009).
Hooff, G. P., Wood, W. G., Muller, W. E. & Eckert, G. P. Isoprenoids, small GTPases and Alzheimer's disease. Biochim. Biophys. Acta 1801, 896–905 (2010).
Liao, J. K. & Laufs, U. Pleiotropic effects of statins. Annu. Rev. Pharmacol. Toxicol. 45, 89–118 (2005).
Cole, S. L. & Vassar, R. Isoprenoids and Alzheimer's disease: a complex relationship. Neurobiol. Dis. 22, 209–222 (2006).
Edlund, C., Soderberg, M., Kristensson, K. & Dallner, G. Ubiquinone, dolichol, and cholesterol metabolism in aging and Alzheimer's disease. Biochem. Cell Biol. 70, 422–428 (1992).
Eckert, G. P. et al. Regulation of the brain isoprenoids farnesyl- and geranylgeranylpyrophosphate is altered in male Alzheimer patients. Neurobiol. Dis. 35, 251–257 (2009).
Zhou, Y. et al. Nonsteroidal anti-inflammatory drugs can lower amyloidogenic Aβ42 by inhibiting Rho. Science 302, 1215–1217 (2003).
Weggen, S., Rogers, M. & Eriksen, J. NSAIDs: small molecules for prevention of Alzheimer's disease or precursors for future drug development? Trends Pharmacol. Sci. 28, 536–543 (2007).
Kukar, T. et al. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Aβ42 production. Nature Med. 11, 545–550 (2005).
Pedrini, S. et al. Modulation of statin-activated shedding of Alzheimer APP ectodomain by ROCK. PLoS Med. 2, 69–78 (2005).
Cole, S. L. et al. Statins cause intracellular accumulation of amyloid precursor protein, β-secretase-cleaved fragments, and amyloid β-peptide via an isoprenoid-dependent mechanism. J. Biol. Chem. 280, 18755–18770 (2005). This study highlights how statins can exert cholesterol-independent effects on the metabolism of APP.
Stokes, C. E. & Hawthorne, J. N. Reduced phosphoinositide concentrations in anterior temporal cortex of Alzheimer-diseased brains. J. Neurochem. 48, 1018–1021 (1987).
Oliveira, T. G. & Di Paolo, G. Phospholipase D in brain function and Alzheimer's disease. Biochim. Biophys. Acta 1801, 799–905 (2010).
Petanceska, S. S. & Gandy, S. The phosphatidylinositol 3-kinase inhibitor wortmannin alters the metabolism of the Alzheimer's amyloid precursor protein. J. Neurochem. 73, 2316–2320 (1999).
Haugabook, S. J. et al. Reduction of Aβ accumulation in the Tg2576 animal model of Alzheimer's disease after oral administration of the phosphatidyl-inositol kinase inhibitor wortmannin. FASEB J. 15, 16–18 (2001).
Di Paolo, G. & De Camilli, P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657 (2006).
Landman, N. et al. Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism. Proc. Natl Acad. Sci. USA 103, 19524–19529 (2006). Along with reference 89, this study connects FAD-associated presenilin mutations with dysregulation of the PLC pathway and PtdIns(4,5)P 2 metabolism.
Yoo, A. S. et al. Presenilin-mediated modulation of capacitative calcium entry. Neuron 27, 561–572 (2000).
Rossner, S. New players in old amyloid precursor protein-processing pathways. Int. J. Dev. Neurosci. 22, 467–474 (2004).
Jenkins, G. M. & Frohman, M. A. Phospholipase D: a lipid centric review. Cell. Mol. Life Sci. 62, 2305–2316 (2005).
Dall'Armi, C. et al. The phospholipase D1 pathway modulates macroautophagy. Nature Commun. 1, 142 (2010).
Cai, D. et al. Presenilin-1 uses phospholipase D1 as a negative regulator of β-amyloid formation. Proc. Natl Acad. Sci. USA 103, 1941–1946 (2006).
Cai, D. et al. Phospholipase D1 corrects impaired βAPP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons. Proc. Natl Acad. Sci. USA 103, 1936–1940 (2006).
Liu, Y. et al. Intracellular trafficking of presenilin 1 is regulated by β-amyloid precursor protein and phospholipase D1. J. Biol. Chem. 284, 12145–12152 (2009).
Ariga, T., McDonald, M. P. & Yu, R. K. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease-a review. J. Lipid Res. 49, 1157–1175 (2008).
Matsuzaki, K., Kato, K. & Yanagisawa, K. Aβ polymerization through interaction with membrane gangliosides. Biochim. Biophys. Acta (2010).
Kracun, I., Kalanj, S., Cosovic, C. & Talan-Hranilovic, J. Brain gangliosides in Alzheimer's disease. J. Hirnforsch. 31, 789–793 (1990).
Kracun, I. et al. Human brain gangliosides in development, aging and disease. Int. J. Dev. Biol. 35, 289–295 (1991).
Yanagisawa, K. Role of gangliosides in Alzheimer's disease. Biochim. Biophys. Acta 1768, 1943–1951 (2007).
Yanagisawa, K., McLaurin, J., Michikawa, M., Chakrabartty, A. & Ihara, Y. Amyloid β-protein (Aβ) associated with lipid molecules: immunoreactivity distinct from that of soluble Aβ. FEBS Lett. 420, 43–46 (1997).
Bernardo, A. et al. Elimination of GD3 synthase improves memory and reduces amyloid-β plaque load in transgenic mice. Neurobiol. Aging 30, 1777–1791 (2009).
Matsuoka, Y. et al. Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to β-amyloid. J. Neurosci. 23, 29–33 (2003).
Salminen, A. & Kaarniranta, K. Siglec receptors and hiding plaques in Alzheimer's disease. J. Mol. Med. 87, 697–701 (2009).
Kamenetz, F. et al. APP processing and synaptic function. Neuron 37, 925–937 (2003).
Cirrito, J. R. et al. Synaptic activity regulates interstitial fluid amyloid-β levels in vivo. Neuron 48, 913–922 (2005).
Lacor, P. N. et al. Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J. Neurosci. 27, 796–807 (2007).
Palop, J. J. & Mucke, L. Amyloid-β-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nature Neurosci. 13, 812–818 (2010).
Green, K. N. & LaFerla, F. M. Linking calcium to Aβ and Alzheimer's disease. Neuron 59, 190–194 (2008).
Wallace, M. A. Effects of Alzheimer's disease-related β amyloid protein fragments on enzymes metabolizing phosphoinositides in brain. Biochim. Biophys. Acta 1227, 183–187 (1994).
Cedazo-Minguez, A., Popescu, B. O., Ankarcrona, M., Nishimura, T. & Cowburn, R. F. The presenilin 1 δE9 mutation gives enhanced basal phospholipase C activity and a resultant increase in intracellular calcium concentrations. J. Biol. Chem. 277, 36646–36655 (2002).
Berman, D. E. et al. Oligomeric amyloid-β peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism. Nature Neurosci. 11, 547–554 (2008). This study provides the first demonstration that amyloid-β disrupts synaptic function by altering the metabolism of Ptd Ins(4,5)P 2 in cultured neurons and hippocampal slices.
Irie, F., Okuno, M., Pasquale, E. B. & Yamaguchi, Y. EphrinB-EphB signalling regulates clathrin-mediated endocytosis through tyrosine phosphorylation of synaptojanin 1. Nature Cell Biol. 7, 501–509 (2005).
Gong, L. W. & De Camilli, P. Regulation of postsynaptic AMPA responses by synaptojanin 1. Proc. Natl Acad. Sci. USA 105, 17561–17566 (2008).
Hsieh, H. et al. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006).
Snyder, E. M. et al. Regulation of NMDA receptor trafficking by amyloid-β. Nature Neurosci. 8, 1051–1058 (2005).
Voronov, S. V. et al. Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down's syndrome. Proc. Natl Acad. Sci. USA 105, 9415–9420 (2008).
Chiang, H. C., Wang, L., Xie, Z., Yau, A. & Zhong, Y. PI3 kinase signaling is involved in Aβ-induced memory loss in Drosophila. Proc. Natl Acad. Sci. USA 107, 7060–7065 (2010).
van Meer, G., Voelker, D. R. & Feigenson, G. W. Membrane lipids: where they are and how they behave. Nature Rev. Mol. Cell Biol. 9, 112–124 (2008).
Stephenson, D. T., Lemere, C. A., Selkoe, D. J. & Clemens, J. A. Cytosolic phospholipase A2 (cPLA2) immunoreactivity is elevated in Alzheimer's disease brain. Neurobiol. Dis. 3, 51–63 (1996).
Prasad, M. R., Lovell, M. A., Yatin, M., Dhillon, H. & Markesbery, W. R. Regional membrane phospholipid alterations in Alzheimer's disease. Neurochem. Res. 23, 81–88 (1998).
Kriem, B. et al. Cytosolic phospholipase A2 mediates neuronal apoptosis induced by soluble oligomers of the amyloid-β peptide. FASEB J. 19, 85–87 (2005).
Malaplate-Armand, C. et al. Soluble oligomers of amyloid-β peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway. Neurobiol. Dis. 23, 178–189 (2006).
Sanchez-Mejia, R. O. et al. Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease. Nature Neurosci. 11, 1311–1318 (2008). This study provides genetic evidence indicating that a calcium-dependent PLA2 isoform and its product arachidonic acid mediate the synaptotoxic effects of β-amyloid.
Sanchez-Mejia, R. O. & Mucke, L. Phospholipase A2 and arachidonic acid in Alzheimer's disease. Biochim. Biophys. Acta 1801, 784–790 (2010).
Oliveira, T. G. et al. Phospholipase d2 ablation ameliorates Alzheimer's disease-linked synaptic dysfunction and cognitive deficits. J. Neurosci. 30, 16419–16428 (2010). This study shows an involvement of PLD2 in the synaptotoxic signalling pathway of amyloid-β using a mouse genetic model.
Raghu, P. et al. Rhabdomere biogenesis in Drosophila photoreceptors is acutely sensitive to phosphatidic acid levels. J. Cell Biol. 185, 129–145 (2009).
Grosgen, S., Grimm, M. O., Friess, P. & Hartmann, T. Role of amyloid β in lipid homeostasis. Biochim. Biophys. Acta 1801, 966–974 (2010).
Puzzo, D. et al. Picomolar amyloid-β positively modulates synaptic plasticity and memory in hippocampus. J. Neurosci. 28, 14537–14545 (2008).
Ryan, S. D. et al. Amyloid-β42 signals tau hyperphosphorylation and compromises neuronal viability by disrupting alkylacylglycerophosphocholine metabolism. Proc. Natl Acad. Sci. USA 106, 20936–20941 (2009).
Nicholson, A. M. & Ferreira, A. Increased membrane cholesterol might render mature hippocampal neurons more susceptible to β-amyloid-induced calpain activation and tau toxicity. J. Neurosci. 29, 4640–4651 (2009).
Johnson, G. V. Tau phosphorylation and proteolysis: insights and perspectives. J. Alzheimers Dis. 9, 243–250 (2006).
de Calignon, A. et al. Caspase activation precedes and leads to tangles. Nature 464, 1201–1204 (2010).
Kawarabayashi, T. et al. Dimeric amyloid β protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer's disease. J. Neurosci. 24, 3801–3809 (2004).
Hernandez, P., Lee, G., Sjoberg, M. & Maccioni, R. B. Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Aβ (25-35): involvement of lipid rafts. J. Alzheimers Dis. 16, 149–156 (2009).
Schenck, A. et al. The endosomal protein Appl1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell 133, 486–497 (2008).
Furuya, T. et al. Negative regulation of Vps34 by Cdk mediated phosphorylation. Mol. Cell 38, 500–511 (2010).
Garcia-Arencibia, M., Hochfeld, W. E., Toh, P. P. & Rubinsztein, D. C. Autophagy, a guardian against neurodegeneration. Semin. Cell Dev. Biol. 21, 691–698 (2010).
Frost, B. & Diamond, M. I. Prion-like mechanisms in neurodegenerative diseases. Nature Rev. Neurosci. 11, 155–159 (2010).
Nixon, R. A. Niemann-Pick Type C disease and Alzheimer's disease: the APP-endosome connection fattens up. Am. J. Pathol. 164, 757–761 (2004).
Nixon, R. A. Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases. Neurobiol. Aging 26, 373–382 (2005).
Jick, H., Zornberg, G. L., Jick, S. S., Seshadri, S. & Drachman, D. A. Statins and the risk of dementia. Lancet 356, 1627–1631 (2000).
Wolozin, B. et al. Simvastatin is associated with a reduced incidence of dementia and Parkinson's disease. BMC Med. 5, 20 (2007).
Arvanitakis, Z. et al. Statins, incident Alzheimer disease, change in cognitive function, and neuropathology. Neurology 70, 1795–1802 (2008).
Feldman, H. H. et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 74, 956–964 (2010). This is a comprehensive study reporting results from clinical trials on the effects of statins in Alzheimer's disease.
Abrahamson, E. E., Ikonomovic, M. D., Dixon, C. E. & DeKosky, S. T. Simvastatin therapy prevents brain trauma-induced increases in β-amyloid peptide levels. Ann. Neurol. 66, 407–414 (2009).
Kandiah, N. & Feldman, H. H. Therapeutic potential of statins in Alzheimer's disease. J. Neurol. Sci. 283, 230–234 (2009).
Durakoglugil, M. S., Chen, Y., White, C. L., Kavalali, E. T. & Herz, J. Reelin signaling antagonizes β-amyloid at the synapse. Proc. Natl Acad. Sci. USA 106, 15938–15943 (2009).
Cole, G. M., Ma, Q. L. & Frautschy, S. A. Omega-3 fatty acids and dementia. Prostaglandins Leukot. Essent. Fatty Acids 81, 213–221 (2009).
Palacios-Pelaez, R., Lukiw, W. J. & Bazan, N. G. Omega-3 essential Fatty acids modulate initiation and progression of neurodegenerative disease. Mol. Neurobiol. 41, 367–374 (2010).
Grimm, M. O. et al. Docosahexaenoic Acid reduces amyloid β production via multiple, pleiotropic mechanism. J Biol. Chem. 15 Feb 2011 (doi:10.1074/jbc.M110.182329).
Bertram, L. & Tanzi, R. E. Genome-wide association studies in Alzheimer's disease. Hum. Mol. Genet. 18, R137–R145 (2009).
Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nature Genet. 41, 1088–1093 (2009).
Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nature Genet. 41, 1094–1099 (2009).
Sanders, A. E. et al. Association of a functional polymorphism in the cholesteryl ester transfer protein (CETP) gene with memory decline and incidence of dementia. JAMA 303, 150–158 (2010).
Wenk, M. R. The emerging field of lipidomics. Nature Rev. Drug Discov. 4, 594–610 (2005). References 134 and 135 highlight the progress and applications of the expanding field of lipidomics.
Piomelli, D., Astarita, G. & Rapaka, R. A neuroscientist's guide to lipidomics. Nature Rev. Neurosci. 8, 743–754 (2007).
Han, X., Holtzman, D. M. & McKeel, D. W. Jr. Plasmalogen deficiency in early Alzheimer's disease subjects and in animal models: molecular characterization using electrospray ionization mass spectrometry. J. Neurochem. 77, 1168–1180 (2001).
Cheng, H., Xu, J., McKeel, D. W. Jr & Han, X. Specificity and potential mechanism of sulfatide deficiency in Alzheimer's disease: an electrospray ionization mass spectrometric study. Cell. Mol. Biol. 49, 809–818 (2003).
Cheng, H., Zhou, Y., Holtzman, D. M. & Han, X. Apolipoprotein E mediates sulfatide depletion in animal models of Alzheimer's disease. Neurobiol. Aging 31, 1188–1196 (2010).
Sharman, M. J. et al. Profiling brain and plasma lipids in human APOE epsilon2, epsilon3, and epsilon4 knock-in mice using electrospray ionization mass spectrometry. J. Alzheimers Dis. 20, 105–111 (2010).
Lingwood, D. & Simons, K. Lipid rafts as a membrane-organizing principle. Science 327, 46–50 (2010).
Lingwood, D., Kaiser, H. J., Levental, I. & Simons, K. Lipid rafts as functional heterogeneity in cell membranes. Biochem. Soc. Trans. 37, 955–960 (2009).
Allen, J. A., Halverson-Tamboli, R. A. & Rasenick, M. M. Lipid raft microdomains and neurotransmitter signalling. Nature Rev. Neurosci. 8, 128–140 (2007).
Jacobson, K., Mouritsen, O. G. & Anderson, R. G. Lipid rafts: at a crossroad between cell biology and physics. Nature Cell Biol. 9, 7–14 (2007).
Ramstedt, B. & Slotte, J. P. Sphingolipids and the formation of sterol-enriched ordered membrane domains. Biochim. Biophys. Acta 1758, 1945–1956 (2006).
Ramstedt, B. & Slotte, J. P. Membrane properties of sphingomyelins. FEBS Lett. 531, 33–37 (2002).
Xu, X. & London, E. The effect of sterol structure on membrane lipid domains reveals how cholesterol can induce lipid domain formation. Biochemistry 39, 843–849 (2000).
Butterfield, D. A. et al. In vivo oxidative stress in brain of Alzheimer disease transgenic mice: requirement for methionine 35 in amyloid β-peptide of APP. Free Radic. Biol. Med. 48, 136–144 (2010).
Schneider, C., Porter, N. A. & Brash, A. R. Routes to 4-hydroxynonenal: fundamental issues in the mechanisms of lipid peroxidation. J. Biol. Chem. 283, 15539–15543 (2008).
Bush, A. I. & Tanzi, R. E. Therapeutics for Alzheimer's disease based on the metal hypothesis. Neurotherapeutics 5, 421–432 (2008).
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.).
The authors declare no competing financial interests.
About this article
Cite this article
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
This article is cited by
Dyslipidemia induced large-scale network connectivity abnormality facilitates cognitive decline in the Alzheimer’s disease
Journal of Translational Medicine (2022)
Alzheimer's Research & Therapy (2022)
Signal Transduction and Targeted Therapy (2022)
Scientific Reports (2022)
Nature Reviews Chemistry (2022)