LIPID RAFTS AND AMYLOID METABOLISM: ROLE IN PATHOGENESIS OF ALZHEIMER’S DISEASE
PDF (English)

Как цитировать

Наливаева, Н. Н., & Turner, A. J. (2020). LIPID RAFTS AND AMYLOID METABOLISM: ROLE IN PATHOGENESIS OF ALZHEIMER’S DISEASE. Российский физиологический журнал им. И. М. Сеченова, 106(5), 539–562. https://doi.org/10.31857/S0869813920050052

Аннотация

Brain lipids play an important role not only as ubiquitous structural membrane components providing the scaffolding and compartmentalisation outside and within the cells but also participating in various signalling processes either by facilitating them or by acting as signal molecules. Membrane lipids form highly specialised domains, called lipid rafts, which are more ordered structures than the rest of the membrane and are enriched in cholesterol and sphingolipids. These domains provide a platform for specific and targeted protein-lipid and protein-protein interactions and as such facilitate binding and/or enzymatic processes on the surface and within the membranes. These lipid-protein interactions are important for various signalling events and proper cell functioning. When normal structure and functions of lipid rafts is disturbed due to the changes in lipid metabolism, caused by various internal and environmental factors, it results in a cascade of pathological events. Among proteins whose metabolic pathways depend on the lipid raft structure and integrity is amyloid precursor protein (APP) – the protein highly implicated in the pathogenesis of Alzheimer’s disease (AD). Proteolytic processing of APP by a metalloproteinase called β-secretase (BACE1) and a multiprotein complex called γ-secretase results in production of the amyloid β peptide (Aβ) - one of the key molecules leading to development of AD. These events take place in the lipid rafts. Some lipid components of the rafts, including ganglioside GM1, facilitate Aβ aggregation and formation of its toxic oligomers. Understanding the mechanisms regulating lipid-protein interactions in the rafts might result in new therapeutic strategies and treatments. In this review we discuss the implications of lipids in APP processing and Aβ metabolism and possible therapeutic avenues derived from studying lipid raft structure and functions in normal and AD brain.

https://doi.org/10.31857/S0869813920050052
PDF (English)

Литература

Hardy J.A., Higgins G.A. Alzheimer's disease: the amyloid cascade hypothesis. Science. 256:184-185. 1992.

Selkoe D.J., Hardy J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol. Med. 8:595-608. 2016. doi: 10.15252/emmm.201606210

Armstrong R.A. Risk factors for Alzheimer's disease. Folia Neuropathol. 57:87-105. 2019. doi: 10.5114/fn.2019.85929

Nelson P.T., Alafuzoff I., Bigio E.H., Bouras C., Braak H., Cairns N.J., Castellani R.J., Crain B.J., Davies P., Del Tredici K., Duyckaerts C., Frosch M.P., Haroutunian V., Hof P.R., Hulette C.M., Hyman B.T., Iwatsubo T., Jellinger K.A., Jicha G.A., Kövari E., Kukull W.A., Leverenz J.B., Love S., Mackenzie I.R., Mann D.M., Masliah E., McKee A.C., Montine T.J., Morris J.C., Schneider J.A., Sonnen J.A., Thal D.R., Trojanowski J.Q., Troncoso J.C., Wisniewski T., Woltjer R.L., Beach T.G. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J. Neuropathol. Exp. Neurol. 71:362-381. 2012. doi: 10.1097/NEN.0b013e31825018f7.

Sakono M., Zako T. Amyloid oligomers: formation and toxicity of Aβ oligomers. FEBS J. 277:1348-1358. 2010. doi 10.1111/j.1742-4658.2010.07568.x.

Walsh D.M., Selkoe D.J. A β oligomers - a decade of discovery. J. Neurochem. 101:1172-1184. doi: 10.1111/j.1471-4159.2006.04426.x.

Yang T., Li S., Xu H., Walsh D.M., Selkoe D.J. Large Soluble Oligomers of Amyloid β-Protein from Alzheimer Brain Are Far Less Neuroactive Than the Smaller Oligomers to Which They Dissociate. J. Neurosci. 37:152-163. 2017. doi: 10.1523/JNEUROSCI.1698-16.2016.

Condello C., Yuan P., Schain A., Grutzendler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6: 6176. 2015. doi: 10.1038/ncomms7176.

Rodríguez-Arellano J.J., Parpura V., Zorec R., Verkhratsky A. Astrocytes in physiological aging and Alzheimer's disease. Neuroscience. 323:170-182. 2016. doi: 10.1016/j.neuroscience.2015.01.007.

Desikan R.S., Sabuncu M.R., Schansky N.J., Reuter M., Cabral H.J., Hess C.P., Weiner M.W., Biffi A., Anderson C.D., Rosand J., Salat D.H., Kemper T.L., Dale A.M., Sperling R.A., Fischl B. Alzheimer's Disease Neuroimaging Initiative. Selective disruption of the cerebral neocortex in Alzheimer's disease. PLoS One. 5:e12853. 2010. doi: 10.1371/journal.pone.0012853.

Carmona S., Hardy J., Guerreiro R. The genetic landscape of Alzheimer disease. Handb. Clin. Neurol. 148:395-408. 2018. doi: 10.1016/B978-0-444-64076-5.00026-0.

Guerreiro R.J., Gustafson D.R., Hardy J. The genetic architecture of Alzheimer's disease: beyond APP, PSENs and APOE. Neurobiol. Aging. 33:437-456. 2012. doi: 10.1016/j.neurobiolaging.2010.03.025.

Hampel H., Vassar R., De Strooper B., Hardy J., Willem M., Singh N., Zhou J., Yan R., Vanmechelen E., De Vos A., Nisticò R., Corbo M., Imbimbo B.P., Streffer J., Voytyuk I., Timmers M., Tahami Monfared A.A., Irizarry M., Albala B., Koyama A., Watanabe N., Kimura T., Yarenis L., Lista S., Kramer L., Vergallo A. The β-secretase BACE1 in Alzheimer’s disease. Biol. Psychiatry. 2020. doi: 10.1016/j.biopsych.2020.02.001.

Haass C., Kaether C., Thinakaran G., Sisodia S. Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med. 2: a006270. 2012. doi: 10.1101/cshperspect.a006270.

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. doi: 10.1083/jcb.200207113.

Cordy J.M., Hussain I., Dingwall C., Hooper N.M., Turner A.J. Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein. Proc. Natl. Acad. Sci. USA. 100:11735-11740. 2003. doi: 10.1073/pnas.1635130100.

Allinson T.M., Parkin E.T., Turner A.J., Hooper N.M. ADAMs family members as amyloid precursor protein alpha-secretases. J. Neurosci. Res. 74:342-352. 2003. doi: 10.1002/jnr.10737.

Hicks D.A., Nalivaeva N.N., Turner A.J. Lipid rafts and Alzheimer's disease: protein-lipid interactions and perturbation of signaling. Front Physiol. 3:189. 2012. doi: 10.3389/fphys.2012.00189.

Bhattacharyya R., Barren C., Kovacs D.M. Palmitoylation of amyloid precursor protein regulates amyloidogenic processing in lipid rafts. J. Neurosci. 33:11169-11183. 2013. doi: 10.1523/JNEUROSCI.4704-12.2013.

Loera-Valencia R., Goikolea J., Parrado-Fernandez C., Merino-Serrais P., Maioli S. Alterations in cholesterol metabolism as a risk factor for developing Alzheimer's disease: Potential novel targets for treatment. J. Steroid. Biochem. Mol. Biol. 190:104-114. 2019. doi: 10.1016/j.jsbmb.2019.03.003. Epub 2019 Mar 13.

Mejías-Trueba M., Pérez-Moreno M.A., Fernández-Arche M.Á. Systematic review of the efficacy of statins for the treatment of Alzheimer's disease. Clin. Med. (Lond). 18:54-61. 2018. doi: 10.7861/clinmedicine.18-1-54.

Hooper N.M., Karran E.H., Turner A.J. Membrane protein secretases. Biochem. J. 321: 265-279. 1997. doi: 10.1042/bj3210265.

Simons K., Ikonen E. Functional rafts in cell membranes. Nature. 387:569-572. 1997. doi: 10.1038/42408.

Sonnino S., Prinetti A. Membrane domains and the "lipid raft" concept. Curr. Med. Chem. 20:4-21. 2013. doi: 10.2174/0929867311320010003.

Bieberich E. Sphingolipids and lipid rafts: Novel concepts and methods of analysis. Chem. Phys. Lipids. 216:114-131. 1918. doi: 10.1016/j.chemphyslip.2018.08.003.

Grassi S., Giussani P., Mauri L., Prioni S., Sonnino S., Prinetti A. Lipid rafts and neurodegeneration: Structural and functional roles in physiologic aging and neurodegenerative diseases. J. Lipid. Res. pii: jlr.TR119000427. 2019. doi: 10.1194/jlr.TR119000427.

Morigaki K., Tanimoto Y. Evolution and development of model membranes for physicochemical and functional studies of the membrane lateral heterogeneity. Biochim. Biophys. Acta Biomembr. 1860:2012-2017. 2018. doi: 10.1016/j.bbamem.2018.03.010.

Rothberg K.G., Heuser J.E., Donzell W.C., Ying Y.S., Glenney J.R., Anderson R.G. Caveolin, a protein component of caveolae membrane coats. Cell. 68:673–682. 1992. doi: 10.1016/0092-8674(92)90143-z.

van Meer G1, Simons K. Lipid polarity and sorting in epithelial cells. J. Cell Biochem. 36:51-58. 1988. doi: 10.1002/jcb.240360106.

Brown D.A., London E. Structure of detergent-resistant membrane domains: does phase separation occur in biological membranes? Biochem. Biophys. Res. Commun. 240:1-7. 1997. doi: 10.1006/bbrc.1997.7575.

Jiang X., Zhu Z., Qin H., Tripathi P., Zhong L., Elsherbini A., Karki S., Crivelli S.M., Zhi W., Wang G., Spassieva S.D., Bieberich E. Visualization of Ceramide-Associated Proteins in Ceramide-Rich Platforms Using a Cross-Linkable Ceramide Analog and Proximity Ligation Assays With Anti-ceramide Antibody. Front Cell Dev. Biol. 7:166. 2019. doi: 10.3389/fcell.2019.00166. eCollection 2019.

Yáñez-Mó M., Gutiérrez-López M.D., Cabañas C. Functional interplay between tetraspanins and proteases. Cell Mol. Life Sci. 68:3323-3335. 2011. doi: 10.1007/s00018-011-0746-y.

Hemler M.E. Tetraspanin functions and associated microdomains. Nat. Rev. Mol. Cell Biol. 6, 801-811. 2005. doi: 10.1038/nrm1736

Moretto E., Longatti A., Murru L., Chamma I., Sessa A., Zapata J., Hosy E., Sainlos M., Saint-Pol J., Rubinstein E., Choquet D., Broccoli V., Schiavo G., Thoumine O., Passafaro M. TSPAN5 Enriched Microdomains Provide a Platform for Dendritic Spine Maturation through Neuroligin-1 Clustering. Cell Rep. 29:1130-1146.e8. 2019. doi: 10.1016/j.celrep.2019.09.051.

Schon E.A., Area-Gomez E. Mitochondria-associated ER membranes in Alzheimer disease.

Mol. Cell Neurosci. 55:26-36. 2013. doi: 10.1016/j.mcn.2012.07.011.

Pera M., Larrea D., Guardia-Laguarta C., Montesinos J., Velasco K.R., Agrawal R.R., Xu Y., Chan R.B., Di Paolo G., Mehler M.F., Perumal G.S., Macaluso F.P., Freyberg Z.Z., Acin-Perez R., Enriquez J.A., Schon E.A., Area-Gomez E. Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J. 36:3356-3371. 2017. doi: 10.15252/embj.201796797.

Hayashi T., Rizzuto R., Hajnoczky G., Su T.P. MAM: more than just a housekeeper.

Trends Cell Biol. 19:81–88. 2009. doi: 10.1016/j.tcb.2008.12.002.

Teixeira G., Vieira L.B., Gomez M.V., Guatimosim C. Cholesterol as a key player in the balance of evoked and spontaneous glutamate release in rat brain cortical synaptosomes. Neurochem. Int. 61:1151-1159. 2012. doi: 10.1016/j.neuint.2012.08.008.

Ouweneel A.B., Thomas M.J., Sorci-Thomas M.G. The ins and outs of lipid rafts: Functions in intracellular cholesterol homeostasis, microparticles, and cell membranes. J. Lipid Res. pii: jlr.TR119000383. 2019. doi: 10.1194/jlr.TR119000383.

Pascual M., Ibáñez F., Guerri C. Exosomes as mediators of neuron-glia communication in neuroinflammation. Neural. Regen. Res. 15:796-801. 2020. doi: 10.4103/1673-5374.268893.

Pollet H., Conrard L., Cloos A.S., Tyteca D. Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding. Biomolecules. 8:pii: E94. 2018. doi: 10.3390/biom8030094.

Turner A.J. PIG-tailed membrane proteins. Essays Biochem. 28:113-127. 1994. PMID: 7925314.

Kinoshita T., Fujita M. Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling. J. Lipid. Res. 571:6-24. 2016. doi: 10.1194/jlr.R063313.

Oh P., Schnitzer J.E. Segregation of heterotrimeric G proteins in cell surface microdomains. G(q) binds caveolin to concentrate in caveolae, whereas G(i) and G(s) target lipid rafts by default. Mol. Biol. Cell. 123:685-698. 2001. doi: 10.1091/mbc.12.3.685.

Snyers L., Umlauf E., Prohaska R. Association of stomatin with lipid-protein complexes in the plasma membrane and the endocytic compartment. Eur. J. Cell Biol. 7811:802-812. 1999. doi: 10.1016/S0171-9335(99)80031-4.

Liu J., Deyoung S.M., Zhang M., Dold L.H., Saltiel A.R. The stomatin/prohibitin/flotillin/HflK/C domain of flotillin-1 contains distinct sequences that direct plasma membrane localization and protein interactions in 3T3-L1 adipocytes. J. Biol. Chem. 28016:16125-16134. 2005. doi: 10.1074/jbc.M500940200.

Schneider A., Rajendran L., Honsho M., Gralle M., Donnert G., Wouters F., Hell S.W., Simons M. Flotillin-dependent clustering of the amyloid precursor protein regulates its endocytosis and amyloidogenic processing in neurons. J. Neurosci. 28:2874-2882. 2008. doi: 10.1523/JNEUROSCI.5345-07.2008.

Morrow I.C., Parton R.G. Flotillins and the PHB domain protein family: rafts, worms and anaesthetics. Traffic. 6:725-740. 2005. doi: 10.1111/j.1600-0854.2005.00318.x.

Parkin E.T., Turner A.J., Hooper N.M. (1999). Amyloid precursor protein, although partially detergent-insoluble in mouse cerebral cortex, behaves as an atypical lipid raft protein. Biochem. J. 344:23-30. 1999. PMCID: PMC1220609.

Kalvodova L., Kahya N., Schwille P., Ehehalt R., Verkade P., Drechsel D., Simons K. Lipids as modulators of proteolytic activity of BACE: involvement of cholesterol, glycosphingolipids, and anionic phospholipids in vitro. J. Biol. Chem. 280: 36815-36823. 2005. doi: 10.1074/jbc.M504484200.

Hur J.Y., Welander H., Behbahani H., Aoki M., Franberg J., Winblad B., Frykman S., Tjernberg L.O. Active γ-secretase is localized to detergent-resistant membranes in human brain. FEBS J. 275:1174-1187. 2008. doi; 10.1111/j.1742-4658.2008.06278.x.

Matsumura N., Takami M., Okochi M., Wada-Kakuda S., Fujiwara H., Tagami S., Funamoto S., Ihara Y., Morishima-Kawashima M. γ-Secretase associated with lipid rafts: multiple interactive pathways in the stepwise processing of β-carboxyl-terminal fragment. J. Biol. Chem. 289:5109-5121. 2014. doi: 10.1074/jbc.M113.510131.

Harris B., Pereira I., Parkin E. Targeting ADAM10 to lipid rafts in neuroblastoma SH-SY5Y cells impairs amyloidogenic processing of the amyloid precursor protein. Brain Res. 1296:203-215. 2009. doi: 10.1016/j.brainres.2009.07.105.

Tellier E., Canault M., Rebsomen L., Bonardo B., Juhan-Vague I., Nalbone G., Peiretti F. The shedding activity of ADAM17 is sequestered in lipid rafts. Exp. Cell. Res.. 312:3969-3980. 2006. doi: 10.1016/j.yexcr.2006.08.027.

Pinheiro T.J. The role of rafts in the fibrillization and aggregation of prions. Chem. Phys. Lipids. 141:66-71. 2006. doi: 10.1016/j.chemphyslip.2006.02.022.

Zhu D., Xiong W.C., Mei L. Lipid rafts serve as a signaling platform for nicotinic acetylcholine receptor clustering. J. Neurosci. 26:4841-4851. 2006. doi: 10.1523/JNEUROSCI.2807-05.2006.

Colón-Sáez J.O., Yakel J.L. The α7 nicotinic acetylcholine receptor function in hippocampal neurons is regulated by the lipid composition of the plasma membrane. J. Physiol. 589:3163-3174. 2011. doi: 10.1113/jphysiol.2011.209494.

Khan G.M., Tong M., Jhun M., Arora K., Nichols R.A. β-Amyloid activates presynaptic α7 nicotinic acetylcholine receptors reconstituted into a model nerve cell system: involvement of lipid rafts. Eur. J. Neurosci. 31:788-796. 2010. doi: 10.1111/j.1460-9568.2010.07116.x.

Moral-Naranjo M.T., Montenegro M.F., Muñoz-Delgado E., Campoy F.J., Vidal C.J. Targeting of acetylcholinesterase to lipid rafts of muscle. Chem. Biol. Interact. 175:312-317. 2008. doi: 10.1016/j.cbi.2008.04.018.

Xie H.Q., Liang D., Leung K.W., Chen V.P., Zhu K.Y., Chan W.K., Choi R.C., Massoulie J., Tsim K.W. Targeting acetylcholinesterase (AChE) to membrane rafts: A function mediated by the proline rich membrane anchor (PRiMA) in neurons. J. Biol. Chem 285: 11537-11546. 2010. doi: 10.1074/jbc.M109.038711.

Suzuki T., Suzuki Y. Virus infection and lipid rafts. Biol. Pharm. Bull. 29:1538-1541. 2006. doi: 10.1248/bpb.29.1538.

Margheri G., D'Agostino R., Trigari S., Sottini S., Del Rosso M. The β-subunit of cholera toxin has a high affinity for ganglioside GM1 embedded into solid supported lipid membranes with a lipid raft-like composition. Lipids. 49:203-206. 2014. doi: 10.1007/s11745-013-3845-8.

Popik W., Alce T.M., Au W.C. Human immunodeficiency virus type 1 uses lipid raft-colocalized CD4 and chemokine receptors for productive entry into CD4(+) T cells. J. Virol. 76:4709-4722. 2002. doi: 10.1128/jvi.76.10.4709-4722.2002.

Lu Y., Liu D.X., Tam J.P. Lipid rafts are involved in SARS-CoV entry into Vero E6 cells. Biochem. Biophys. Res. Commun. 369:344-349. 2008. doi: 10.1016/j.bbrc.2008.02.023.

Yan R., Zhang Y., Li Y., Xia L., Guo Y., Zhou Q. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. pii: eabb2762. 2020. doi: 10.1126/science.abb2762.

Riemann D., Hansen G.H., Niels-Christiansen L., Thorsen E., Immerdal L., Santos A.N., Kehlen A., Langner J., Danielsen E.M. Caveolae/lipid rafts in fibroblast-like synoviocytes: ectopeptidase-rich membrane microdomains. Biochem. J. 354:47-55. 2001. doi: 10.1042/0264-6021:3540047.

Sato K., Tanabe C., Yonemura Y., Watahiki H., Zhao Y., Yagishita S., Ebina M., Suo S., Futai E., Murata M., Ishiura S. Localization of mature neprilysin in lipid rafts. J. Neurosci. Res. 90:870-877. 2012. doi: 10.1002/jnr.22796.

Grider M.H., Park D., Spencer D.M., Shine H.D. Lipid raft-targeted Akt promotes axonal branching and growth cone expansion via mTOR and Rac1, respectively. J. Neurosci. Res. 87:3033-3042. 2009. doi: 10.1002/jnr.22140.

Petro K.A., Schengrund C.L. Membrane raft disruption promotes axonogenesis in n2a neuroblastoma cells. Neurochem. Res 34:29-37. 2009. doi: 10.1007/s11064-008-9625-9.

Willmann R., Pun S., Stallmach L., Sadasivam G., Santos A.F., Caroni P., Fuhrer C. Cholesterol and lipid microdomains stabilize the postsynapse at the neuromuscular junction. EMBO J. 25:4050-4060. 2006. doi: 10.1038/sj.emboj.7601288.

Nalivaeva N.N., Turner A.J. The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett. 587:2046-2054. 2013. doi: 10.1016/j.febslet.2013.05.010.

Kitaguchi N., Takahashi Y., Tokushima Y., Shiojiri S., Ito H. (1988). Novel precursor of Alzheimer's disease amyloid protein shows protease inhibitory activity. Nature. 331:530-532. doi: 10.1038/331530a0.

Sandbrink R., Masters C.L., Beyreuther K. APP gene family. Alternative splicing generates functionally related isoforms. Ann. NY Acad. Sci. 777:281-287. 1996. doi: 10.1111/j.1749-6632.1996.tb34433.x

Tanaka S., Shiojiri S., Takahashi Y., Kitaguchi N., Ito H., Kameyama M., Kimura J., Nakamura S., Ueda K. Tissue-specific expression of three types of β-protein precursor mRNA: enhancement of protease inhibitor-harboring types in Alzheimer’s disease brain. Biochem. Biophys. Res. Commun. 165:1406–1414. 1989. doi: 10.1016/0006-291x(89)92760-5.

Golde T.E., Estus S., Usiak M., Younkin L.H., Younkin S.G. Expression of β amyloid protein precursor mRNAs: recognition of a novel alternatively spliced form and quantitation in Alzheimer's disease using PCR. Neuron. 4:253-267. 1990. doi: 10.1016/0896-6273(90)90100-t.

Moir R.D., Lynch T., Bush A.I., Whyte S., Henry A., Portbury S., Multhaup G., Small D.H., Tanzi R.E., Beyreuther K., Masters C.L. Relative increase in Alzheimer’s disease of soluble forms of cerebral Ab amyloid protein precursor containing the Kunitz protease inhibitory domain. J. Biol. Chem. 273:5013–5019. 1998. doi: 10.1074/jbc.273.9.5013.

Yamada T., Araki E., Izumi R., Goto I., Sasaki H., Sakaki Y. Expression of Alzheimer amyloid β-protein precursor gene in neuronal cells. Gerontology. 37(Suppl 1):24-30. 1991. doi: 10.1159/000213294.

Zhang H., Ma Q., Zhang Y.W., Xu H. Proteolytic processing of Alzheimer’s β-amyloid precursor protein. J. Neurochem. 120(Suppl 1):9–21. doi: 10.1111/j.1471-4159.2011.07519.x.

Chasseigneaux S., Allinquant B. Functions of Aβ, sAPPα and sAPPβ : similarities and differences. J. Neurochem. 120(Suppl 1):99-108. doi: 10.1111/j.1471-4159.2011.07584.x.

Octave J.N., Pierrot N., Ferao Santos S., Nalivaeva N.N., Turner A.J. From synaptic spines to nuclear signaling: nuclear and synaptic actions of the amyloid precursor protein. J. Neurochem. 126:183-190. 2013. doi: 10.1111/jnc.12239.

Higgins L.S., Murphy G.M., Jr., Forno L.S., Catalano R., Cordell B. P3 β-amyloid peptide has a unique and potentially pathogenic immunohistochemical profile in Alzheimer’s disease brain. Am. J. Pathol. 149:585–596. 1996. PMCID: PMC1865300.

Siegel G., Gerber H., Koch P., Bruestle O., Fraering P.C., Rajendran L. The Alzheimer's Disease γ-Secretase Generates Higher 42:40 Ratios for β-Amyloid Than for p3 Peptides. Cell. Rep. 19:1967-1976. doi: 10.1016/j.celrep.2017.05.034.

Lefranc-Jullien S., Sunyach C., Checler F. APPε, the ε-secretase-derived N-terminal product of the β-amyloid precursor protein, behaves as a type I protein and undergoes α-, β-, and γ-secretase cleavages. J. Neurochem. 97:807-817. 2006. doi: 10.1111/j.1471-4159.2006.03748.x.

Haupt S., Borghese L., Brüstle O., Edenhofer F. Non-genetic modulation of Notch activity by artificial delivery of Notch intracellular domain into neural stem cells. Stem. Cell. Rev. Rep. 8:672-684. 2012. doi: 10.1007/s12015-011-9335-6.

Sawamura N., Ko M., Yu W., Zou K., Hanada K., Suzuki T., Gong J.S., Yanagisawa K., Michikawa M. Modulation of amyloid precursor protein cleavage by cellular sphingolipids. J. Biol. Chem. 279:11984-11991. 2004. doi: 10.1074/jbc.M309832200.

Cordy J.M., Hooper N.M., Turner A.J. The involvement of lipid rafts in Alzheimer's disease. Mol. Membr.Biol. 23:111-122. 2006. doi: 10.1080/09687860500496417.

Vetrivel K.S., Thinakaran G. Membrane rafts in Alzheimer's disease β-amyloid production. Biochim. Biophys. Acta. 1801:860-867. 2010. doi: 10.1016/j.bbalip.2010.03.007.

Chen T.Y., Liu P.H., Ruan C.T., Chiu L., Kung F.L. The intracellular domain of amyloid precursor protein interacts with flotillin-1, a lipid raft protein. Biochem. Biophys. Res. Commun. 342:266-272. 2006. doi: 10.1016/j.bbrc.2006.01.156.

Beel A.J., Sakakura M., Barrett P.J., Sanders C.R. Direct binding of cholesterol to the amyloid precursor protein: An important interaction in lipid-Alzheimer's disease relationships? Biochim. Biophys. Acta. 1801:975-982. 2010. doi: 10.1016/j.bbalip.2010.03.008.

Yao Z.X., Papadopoulos V. Function of β-amyloid in cholesterol transport: a lead to neurotoxicity. FASEB J. 16:1677-1679. 2002. doi: 10.1096/fj.02-0285fje.

Minami S.S., Hoe H.S., Rebeck G.W. Fyn kinase regulates the association between amyloid precursor protein and Dab1 by promoting their localization to detergent-resistant membranes. J. Neurochem. 118:879-890. 2011. doi: 10.1111/j.1471-4159.2011.07296.x.

Watanabe T., Hikichi Y., Willuweit A., Shintani Y., Horiguchi T. FBL2 regulates amyloid precursor protein (APP) metabolism by promoting ubiquitination-dependent APP degradation and inhibition of APP endocytosis. J. Neurosci. 32:3352-3365. 2012. doi: 10.1523/JNEUROSCI.5659-11.2012.

Yoon I.S., Chen E., Busse T., Repetto E., Lakshmana M.K., Koo E.H., Kang D.E. Low-density lipoprotein receptor-related protein promotes amyloid precursor protein trafficking to lipid rafts in the endocytic pathway. FASEB J. 21:2742-2752. 2007. doi: 10.1096/fj.07-8114com.

Fuentealba R.A., Barría M.I., Lee J., Cam J., Araya C., Escudero C.A., Inestrosa N.C., Bronfman F.C., Bu G., Marzolo M.P. ApoER2 expression increases Aβ production while decreasing Amyloid Precursor Protein (APP) endocytosis: Possible role in the partitioning of APP into lipid rafts and in the regulation of γ-secretase activity. Mol. Neurodegener. 2:14. 2007. doi: 10.1186/1750-1326-2-14.

Bhattacharyya R., Fenn R.H., Barren C., Tanzi R.E., Kovacs D.M. Palmitoylated APP Forms Dimers, Cleaved by BACE1. PLoS One. 11:e0166400. 2016. doi: 10.1371/journal.pone.0166400.

Head B.P., Patel H.H., Insel P.A. Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim. Biophys. Acta. 1838:532-545. 2014. doi: 10.1016/j.bbamem.2013.07.018.

Rushworth J.V., Hooper N.M. Lipid Rafts: Linking Alzheimer's Amyloid-β Production, Aggregation, and Toxicity at Neuronal Membranes. Int. J. Alzheimers Dis. 2011:603052. 2010. doi: 10.4061/2011/603052.

Kim S.I., Yi J.S., Ko Y.G. Amyloid β oligomerization is induced by brain lipid rafts. J. Cell Biochem. 99:878-889. 2006. doi: 10.1002/jcb.20978.

Ikeda K., Yamaguchi T., Fukunaga S., Hoshino M., Matsuzaki K. Mechanism of amyloid β-protein aggregation mediated by GM1 ganglioside clusters. Biochemistry. 50:6433-6440. 2011. doi: 10.1021/bi200771m.

Ogawa M., Tsukuda M., Yamaguchi T., Ikeda K., Okada T., Yano Y., Hoshino M., Matsuzaki K. Ganglioside-mediated aggregation of amyloid β-proteins (Aβ): comparison between Aβ-(1-42) and Aβ-(1-40). J. Neurochem. 116:851-857. 2011. doi: 10.1111/j.1471-4159.2010.06997.x.

Hattori C., Asai M., Onishi H., Sasagawa N., Hashimoto Y., Saido T.C., Maruyama K., Mizutani S., Ishiura S. BACE1 interacts with lipid raft proteins. J. Neurosci.Res. 84:912-917. 2006. doi: 10.1002/jnr.20981.

Motoki K., Kume H., Oda A., Tamaoka A., Hosaka A., Kametani F., Araki W. Neuronal β-amyloid generation is independent of lipid raft association of β-secretase BACE1: analysis with a palmitoylation-deficient mutant. Brain Behav. 2:270-282. 2012. doi: 10.1002/brb3.52.

Ebina M., Futai E., Tanabe C., Sasagawa N., Kiso Y., Ishiura S. Inhibition by KMI-574 leads to dislocalization of BACE1 from lipid rafts. J. Neurosci. Res. 87:360–368. 2009. doi: 10.1002/jnr.21858.

Vetrivel K.S., Barman A., Chen Y., Nguyen P.D., Wagner S.L., Prabhakar R., Thinakaran G. Loss of cleavage at β'-site contributes to apparent increase in β-amyloid peptide (Aβ) secretion by β-secretase (BACE1)-glycosylphosphatidylinositol (GPI) processing of amyloid precursor protein. J. Biol. Chem. 286:26166-26177. 2011. doi: 10.1074/jbc.M111.260471.

Parkin E.T., Watt N.T., Hussain I., Eckman E.A., Eckman C.B., Manson J.C., Baybutt H.N., Turner A.J., Hooper N.M. Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein. Proc. Natl. Acad. Sci. USA. 104:11062-11067. 2007. doi: 10.1073/pnas.0609621104.

Griffiths H.H., Whitehouse I.J., Baybutt H., Brown D., Kellett K.A., Jackson C.D., Turner A.J., Piccardo P., Manson J.C., Hooper N.M. Prion protein interacts with BACE1 protein and differentially regulates its activity toward wild type and Swedish mutant amyloid precursor protein. J. Biol. Chem. 286:33489-33500. 2011. doi: 10.1074/jbc.M111.278556.

Vetrivel K.S., Cheng H., Lin W., Sakurai T., Li T., Nukina N., Wong P.C., Xu H., Thinakaran G. Association of γ-secretase with lipid rafts in post-Golgi and endosome membranes. J. Biol. Chem. 279:44945-54. 2004. doi: 10.1074/jbc.M407986200.

Cheng H., Vetrivel K.S., Drisdel R.C., Meckler X., Gong P., Leem J.Y., Li T., Carter M., Chen Y., Nguyen P., Iwatsubo T., Tomita T., Wong P.C., Green W.N., Kounnas M.Z., Thinakaran G. S-palmitoylation of gamma-secretase subunits nicastrin and APH-1. J. Biol. Chem. 284:1373-84. 2009. doi: 10.1074/jbc.M806380200.

Kapoor A., Hsu W.M., Wang B.J., Wu G.H., Lin T.Y., Lee S.J., Yen C.T., Liang S.M., Liao Y.F. Caveolin-1 regulates γ-secretase-mediated AβPP processing by modulating spatial distribution of γ-secretase in membrane. J. Alzheimers Dis. 22: 423-242. 2010. doi: 10.3233/JAD-2010-100531.

Kim Y., Kim C., Jang H.Y., Mook-Jung I. Inhibition of Cholesterol Biosynthesis Reduces γ-Secretase Activity and Amyloid-β Generation. J. Alzheimers Dis. 51:1057-1068. 2016. doi: 10.3233/JAD-150982.

Eckert G.P., Müller W.E. Presenilin 1 modifies lipid raft composition of neuronal membranes. Biochem. Biophys. Res. Commun. 382:673-677. 2009. doi: 10.1016/j.bbrc.2009.03.070.

Han J., Jung S., Jang J., Kam T.I., Choi H., Kim B.J., Nah J., Jo D.G., Nakagawa T., Nishimura M., Jung Y.K. OCIAD2 activates γ-secretase to enhance amyloid β production by interacting with nicastrin. Cell. Mol. Life Sci. 71:2561-2576. 2014. doi: 10.1007/s00018-013-1515-x.

Xu D., Sharma C., Hemler M.E. Tetraspanin12 regulates ADAM10-dependent cleavage of amyloid precursor protein. FASEB J. 23:3674-3681. 2009. doi: 10.1096/fj.09-133462.

Seipold L., Saftig P. The Emerging Role of Tetraspanins in the Proteolytic Processing of the Amyloid Precursor Protein. Front Mol. Neurosci. 9:149. 2016. doi: 10.3389/fnmol.2016.00149.

Seipold L., Damme M., Prox J., Rabe B., Kasparek P., Sedlacek R., Altmeppen H., Willem M., Boland B., Glatzel M., Saftig P. Tetraspanin 3: A central endocytic membrane component regulating the expression of ADAM10, presenilin and the amyloid precursor protein. Biochim. Biophys. Acta Mol. Cell. Res. 1864:217-230. 2017. doi: 10.1016/j.bbamcr.2016.11.003.

Belyaev N.D., Kellett K.A., Beckett C., Makova N.Z., Revett T.J., Nalivaeva N.N., Hooper N.M., Turner A.J. The transcriptionally active amyloid precursor protein (APP) intracellular domain is preferentially produced from the 695 isoform of APP in a β-secretase-dependent pathway J. Biol. Chem. 285:41443-41454. 2010. doi: 10.1074/jbc.M110.141390.

Lorenzen A., Samosh J., Vandewark K., Anborgh P.H., Seah C., Magalhaes A.C., Cregan S.P., Ferguson S.S., Pasternak S.H. Rapid and direct transport of cell surface APP to the lysosome defines a novel selective pathway. Mol. Brain 3:11. 2010. doi: 10.1186/1756-6606-3-11.

Yang M., Virassamy B., Vijayaraj S.L., Lim Y., Saadipour K., Wang Y.J., Han Y.C., Zhong J.H., Morales C.R., Zhou X.F. The intracellular domain of sortilin interacts with amyloid precursor protein and regulates its lysosomal and lipid raft trafficking. PLoS One. 8:e63049. 2013. doi: 10.1371/journal.pone.0063049. Print 2013.

Miranda A.M., Lasiecka Z.M., Xu Y., Neufeld J., Shahriar S., Simoes S., Chan R.B., Oliveira T.G., Small S.A., Di Paolo G. Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures. Nat. Commun. 9:291. 2018. doi: 10.1038/s41467-017-02533-w.

Lauritzen I., Bécot A., Bourgeois A., Pardossi-Piquard R., Biferi M.G., Barkats M., Checler F. Targeting γ-secretase triggers the selective enrichment of oligomeric APP-CTFs in brain extracellular vesicles from Alzheimer cell and mouse models. Transl. Neurodegener. 8:35. 2019. doi: 10.1186/s40035-019-0176-6.

Rosas-Hernandez H., Cuevas E., Raymick J.B., Robinson B.L., Ali S.F., Hanig J., Sarkar S. Characterization of Serum Exosomes from a Transgenic Mouse Model of Alzheimer's Disease. Curr. Alzheimer Res. 16:388-395. 2019. doi: 10.2174/1567205016666190321155422.

Beckett, Nalivaeva N.N., Belyaev N.D., Turner A.J. Nuclear signalling by membrane protein intracellular domains: the AICD enigma. Cell Signal. 24:402-409. 2012. doi: 10.1016/j.cellsig.2011.10.007.

Pardossi-Piquard R., Petit A., Kawarai T., Sunyach C., Alves da Costa C., Vincent B., Ring S., D'Adamio L., Shen J., Muller U., St George Hyslop P., Checler F. Presenilin-dependent transcriptional control of the Aβ-degrading enzyme neprilysin by intracellular domains of βAPP and APLP. Neuron. 46:541-554. 2005. doi: 10.1016/j.neuron.2005.04.008.

Belyaev N.D., Nalivaeva N.N., Makova N.Z., Turner A.J. Neprilysin gene expression requires binding of the amyloid precursor protein intracellular domain to its promoter: implications for Alzheimer disease. EMBO Rep. 10:94-100. 2009. doi: 10.1038/embor.2008.222.

Pardossi-Piquard R., Checler F. The physiology of the β-amyloid precursor protein intracellular domain AICD. J. Neurochem. 120(Suppl 1):109-124. 2012. doi: 10.1111/j.1471-4159.2011.07475.x.

Nalivaeva N.N., Belyaev N.D., Kerridge C., Turner A.J. Amyloid-clearing proteins and their epigenetic regulation as a therapeutic target in Alzheimer's disease. Front Aging Neurosci. 6:235. 2014. doi: 10.3389/fnagi.2014.00235.

Kerridge C., Belyaev N.D., Nalivaeva N.N., Turner A.J. The Aβ-clearance protein transthyretin, like neprilysin, is epigenetically regulated by the amyloid precursor protein intracellular domain. J. Neurochem. 130:419-431. 2014. doi: 10.1111/jnc.12680.

von Rotz R.C., Kohli B.M., Bosset J., Meier M., Suzuki T., Nitsch R.M., Konietzko U. The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor. J. Cell Sci. 117:4435-4448. 2004. doi: 10.1242/jcs.01323.

Grimm M.O., Rothhaar T.L., Hartmann T. The role of APP proteolytic processing in lipid metabolism. Exp. Brain Res. 217:365-375. 2012. doi: 10.1007/s00221-011-2975-6.

Grimm M.O., Grösgen S., Rothhaar T.L., Burg V.K., Hundsdörfer B., Haupenthal V.J., Friess P., Müller U., Fassbender K., Riemenschneider M., Grimm H.S., Hartmann T. Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease. Int. J. Alzheimers Dis. 2011:695413. 2011. doi: 10.4061/2011/695413.

Liu Q., Zerbinatti C.V., Zhang J., Hoe H.S., Wang B., Cole S.L., Herz J., Muglia L., Bu G. Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1. Neuron. 56:66-78. 2007. doi: 10.1016/j.neuron.2007.08.008.

Hama E., Shirotani K., Iwata N., Saido T.C. Effects of neprilysin chimeric proteins targeted to subcellular compartments on amyloid β peptide clearance in primary neurons. J. Biol. Chem. 279:30259-30264. 2004. doi: 10.1074/jbc.M401891200.

Bulloj A., Leal M.C., Surace E.I., Zhang X., Xu H., Ledesma M.D., Castaño E.M., Morelli L. Detergent resistant membrane-associated IDE in brain tissue and cultured cells: Relevance to Aβ and insulin degradation. Mol. Neurodegener. 3:22. 2008. doi: 10.1186/1750-1326-3-22.

Kreps E.M., Avrova N.F., Chebotarëva M.A., Chirkovskaya E.V., Levitina M.V., Pomazanskaya L.F., Pravdina N.I. Some aspects of comparative biochemistry of brain lipids in teleost and elasmobranch fish. Comp. Biochem. Physiol. B. 52:293-299. 1975. doi: 10.1016/0305-0491(75)90067-x.

Santos G., Díaz M., Torres N.V. Lipid Raft Size and Lipid Mobility in Non-raft Domains Increase during Aging and Are Exacerbated in APP/PS1 Mice Model of Alzheimer's Disease. Predictions from an Agent-Based Mathematical Model. Front Physiol. 7:90. 2016. doi: 10.3389/fphys.2016.00090.

Quinto- Marin R., Fabelo N., Fernández-Echevarría C., Canerina-Amaro A., Rodríguez-Barreto D., Alemany D., Mesa-Herrera F., Díaz M. Lipid Raft Alterations in Aged-Associated Neuropathologies. Curr. Alzheimer Res. 13:973-984. 2016. doi: 10.2174/1567205013666160314150017.

Varma V.R., Oommen A.M., Varma S., Casanova R., An Y., Andrews R.M., O'Brien R., Pletnikova O., Troncoso J.C., Toledo J., Baillie R., Arnold M., Kastenmueller G., Nho K., Doraiswamy P.M., Saykin A.J., Kaddurah-Daouk R., Legido-Quigley C., Thambisetty M. Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study. PLoS Med. 15:e1002482. 2018. doi: 10.1371/journal.pmed.1002482.

Kinoshita M., Suzuki K.G.N., Murata M., Matsumori N. Evidence of lipid rafts based on the partition and dynamic behavior of sphingomyelins. Chem. Phys. Lipids. 215:84-95. 2018. doi: 10.1016/j.chemphyslip.2018.07.002.

Herget T., Esdar C., Oehrlein S.A., Heinrich M., Schütze S., Maelicke A., van Echten-Deckert G. Production of ceramides causes apoptosis during early neural differentiation in vitro. J. Biol. Chem. 275:30344-30354. 2000. 10.1074/jbc.M000714200.

Nalivaeva N.N., Rybakina E.G., Pivanovich I.Yu., Kozinets I.A., Shanin S.N., Bartfai T. Activation of neutral sphingomyelinase by IL-1β requires the type 1 interleukin 1 receptor. Cytokine. 12:229-232. 2000. doi: 10.1006/cyto.1999.0547.

Clement A.B., Gamerdinger M., Tamboli I.Y., Lütjohann D., Walter J., Greeve I., Gimpl G., Behl C. Adaptation of neuronal cells to chronic oxidative stress is associated with altered cholesterol and sphingolipid homeostasis and lysosomal function. J. Neurochem. 111:669-682. 2009. doi: 10.1111/j.1471-4159.2009.06360.x.

Mahfoud R., Garmy N., Maresca M., Yahi N., Puigserver A., Fantini J. Identification of a common sphingolipid-binding domain in Alzheimer, prion, and HIV-1 proteins. J. Biol. Chem. 277:11292-11296. 2002. doi: 10.1074/jbc.M111679200.

Han X., Rozen S., Boyle S.H., Hellegers C., Cheng H., Burke J.R., Welsh-Bohmer K.A., Doraiswamy P.M., Kaddurah-Daouk R. Metabolomics in early Alzheimer's disease: identification of altered plasma sphingolipidome using shotgun lipidomics. PLoS One. 6: e21643. 2011. doi: 10.1371/journal.pone.0021643.

Grimm M.O., Grimm H.S., Pätzold A.J., Zinser E.G., Halonen R., Duering M., Tschäpe J.A., De Strooper B., Müller U., Shen J., Hartmann T. Regulation of cholesterol and sphingomyelin metabolism by amyloid-β and presenilin. Nat. Cell. Biol. 7:1118-1123. 2005. 10.1038/ncb1313.

Jana A., Pahan K. Fibrillar amyloid-β-activated human astroglia kill primary human neurons via neutral sphingomyelinase: implications for Alzheimer's disease. J. Neurosci. 30:12676-12689. 2010. doi: 10.1523/JNEUROSCI.1243-10.2010.

Haughey N.J., Bandaru V.V., Bae M., Mattson M.P. Roles for dysfunctional sphingolipid metabolism in Alzheimer's disease neuropathogenesis. Biochim. Biophys. Acta. 1801:878-886. 2010. doi: 10.1016/j.bbalip.2010.05.003.

Bienias K., Fiedorowicz A., Sadowska A., Prokopiuk S., Car H. Regulation of sphingomyelin metabolism. Pharmacol. Rep. 68:570-581. 2016. doi: 10.1016/j.pharep.2015.12.008.

Lu M.H., Ji W.L., Xu D.E., Yao P.P., Zhao X.Y., Wang Z.T., Fang L.P., Huang R., Lan L.J., Chen J.B., Wang T.H., Cheng L.H., Xu R.X., Liu C.F., Puglielli L., Ma Q.H. Inhibition of sphingomyelin synthase 1 ameliorates alzheimer-like pathology in APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1. Exp. Neurol. 311:67-79. 2019. doi: 10.1016/j.expneurol.2018.09.012.

Stoffel W., Jenke B., Schmidt-Soltau I., Binczek E., Brodesser S., Hammels I. SMPD3 deficiency perturbs neuronal proteostasis and causes progressive cognitive impairment. Cell. Death Dis. 9:507. 2018. doi: 10.1038/s41419-018-0560-7.

Couttas T.A., Kain N., Tran C., Chatterton Z., Kwok J.B., Don A.S. Age-Dependent Changes to Sphingolipid Balance in the Human Hippocampus are Gender-Specific and May Sensitize to Neurodegeneration. J. Alzheimers Dis. 63:503-514. 2018. doi: 10.3233/JAD-171054.

Furukawa K., Ohmi Y., Ohkawa Y., Tokuda N., Kondo Y., Tajima O., Furukawa K. Regulatory mechanisms of nervous systems with glycosphingolipids. Neurochem. Res. 36:1578-1586. 2011. doi: 10.1007/s11064-011-0494-2.

Kracun I., Rosner H., Drnovsek V., Heffer-Lauc M., Cosović C., Lauc G. Human brain gangliosides in development, aging and disease. Int. J. Dev. Biol. 35:289-295. 1991. PMID: 1814411.

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. doi: 10.1194/jlr.R800007-JLR200.

Kalanj S., Kracun I., Rosner H., Cosović C. Regional distribution of brain gangliosides in Alzheimer's disease. Neurol. Croat. 40:269-281. 1991. PMID: 1751644.

Molander-Melin M., Blennow K., Bogdanovic N., Dellheden B., Månsson J.E., Fredman P. Structural membrane alterations in Alzheimer brains found to be associated with regional disease development; increased density of gangliosides GM1 and GM2 and loss of cholesterol in detergent-resistant membrane domains. J. Neurochem. 92:171-182. 2005. doi: 10.1111/j.1471-4159.2004.02849.x

Nishinaka T., Iwata D., Shimada S., Kosaka K., Suzuki Y. Anti-ganglioside GD1a monoclonal antibody recognizes senile plaques in the brains of patients with Alzheimer-type dementia. Neurosci. Res. 17:171-176. 1993. doi: 10.1016/0168-0102(93)90093-6.

Chan R.B., Oliveira T.G., Cortes E.P., Honig L.S., Duff K.E., Small S.A., Wenk M.R., Shui G., Di Paolo G.J. Comparative lipidomic analysis of mouse and human brain with Alzheimer disease. Biol. Chem. 287:2678-2688. 2012. doi: 10.1074/jbc.M111.274142.

Suzuki K.G.N., Ando H., Komura N., Fujiwara T., Kiso M., Kusumi A. Unraveling of Lipid Raft Organization in Cell Plasma Membranes by Single-Molecule Imaging of Ganglioside Probes. Adv. Exp. Med. Biol. 1104:41-58. 2018. doi: 10.1007/978-981-13-2158-0_3.

Matsuzaki K. Aβ-ganglioside interactions in the pathogenesis of Alzheimer's disease. Biochim. Biophys. Acta Biomembr. 3:183233. doi: 10.1016/j.bbamem.2020.183233.

Lemkul J.A., Bevan D.R. Lipid composition influences the release of Alzheimer's amyloid β-peptide from membranes. Protein Sci. 20:1530-1545. 2011. doi: 10.1002/pro.678.

Kakio A., Nishimoto S.I., Yanagisawa K., Kozutsumi Y., Matsuzaki K. Cholesterol-dependent formation of GM1 ganglioside-bound amyloid β-protein, an endogenous seed for Alzheimer amyloid. J. Biol. Chem. 276:24985-24990. 2001. doi: 10.1074/jbc.M100252200.

Zha Q., Ruan Y., Hartmann T., Beyreuther K., Zhang D. GM1 ganglioside regulates the proteolysis of amyloid precursor protein. Mol. Psychiatry. 9:946-952. 2004. doi: 10.1038/sj.mp.4001509.

Peters I., Igbavboa U., Schütt T., Haidari S., Hartig U., Rosello X., Böttner S., Copanaki E., Deller T., Kögel D., Wood W.G., Müller W.E., Eckert G.P. The interaction of β-amyloid protein with cellular membranes stimulates its own production. Biochim. Biophys. Acta. 1788:964-972. 2009. doi: 10.1016/j.bbamem.2009.01.012.

Yamamoto N., Igbabvoa U., Shimada Y., Ohno-Iwashita Y., Kobayashi M., Wood W.G., Fujita S.C., Yanagisawa K. Accelerated Aβ aggregation in the presence of GM1-ganglioside-accumulated synaptosomes of aged apoE4-knock-in mouse brain. FEBS Lett. 569:135-139. 2004. doi: 10.1016/j.febslet.2004.05.037.

Grimm M.O., Zinser E.G., Grösgen S., Hundsdörfer B., Rothhaar T.L., Burg V.K., Kaestner L., Bayer T.A., Lipp P., Müller U., Grimm H.S., Hartmann T. Amyloid precursor protein (APP) mediated regulation of ganglioside homeostasis linking Alzheimer's disease pathology with ganglioside metabolism. PLoS One. 7:e34095. 2012. doi: 10.1371/journal.pone.0034095.

Svennerholm L., Bråne G., Karlsson I., Lekman A., Ramström I., Wikkelsö C. Alzheimer disease - effect of continuous intracerebroventricular treatment with GM1 ganglioside and a systematic activation programme. Dement. Geriatr. Cogn. Disord. 14:128-136. 2002. doi: 10.1159/000063604.

Dai R., Zhang S., Duan W., Wei R., Chen H., Cai W., Yang L., Wang Q. Enhanced autophagy contributes to protective effects of GM1 ganglioside against Aβ1-42-induced neurotoxicity and cognitive deficits. Neurochem. Res. 42:2417–2426. 2017. doi: 10.1007/s11064-017-2266-0.

Yuyama K., Sun H., Sakai S., Mitsutake S., Okada M., Tahara H., Furukawa J., Fujitani N., Shinohara Y., Igarashi Y. Decreased amyloid-β pathologies by intracerebral loading of glycosphingolipid-enriched exosomes in Alzheimer model mice. J. Biol. Chem. 289:24488–24498. 2014. doi: 10.1074/jbc.M114.577213.

Matsuoka Y., Saito M., LaFrancois J., Saito M., Gaynor K., Olm V., Wang L., Casey E., Lu Y., Shiratori C., Lemere C., Duff K. 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. doi: 10.1523/JNEUROSCI.23-01-00029.2003.

Goodfellow J.A., Willison H.J. Gangliosides and Autoimmune Peripheral Nerve Diseases. Prog Mol Biol Transl Sci. 156:355-382. 2018. doi: 10.1016/bs.pmbts.2017.12.010.

Magistretti P.J., Geisler F.H., Schneider J.S., Li P.A., Fiumelli H., Sipione S. Gangliosides: Treatment Avenues in Neurodegenerative Disease. Front Neurol. 10:859. 2019. doi: 10.3389/fneur.2019.00859.

Allinquant B., Clamagirand C., Potier M.C. Role of cholesterol metabolism in the pathogenesis of Alzheimer's disease. Curr. Opin. Clin. Nutr. Metab. Care. 17:319-323. 2014. doi: 10.1097/MCO.0000000000000069.

Eckert G.P., Hooff G.P., Strandjord D.M., Igbavboa U., Volmer D.A., Müller W.E., Wood W.G. Regulation of the brain isoprenoids farnesyl- and geranylgeranylpyrophosphate is altered in male Alzheimer patients. Neurobiol. Dis. 35:251–257. 2009. 10.1016/j.nbd.2009.05.005.

Cho Y.Y., Kwon O.H., Park M.K., Kim T.W., Chung S. Elevated cellular cholesterol in Familial Alzheimer's presenilin 1 mutation is associated with lipid raft localization of β-amyloid precursor protein. PLoS One. 14:e0210535. 2019. doi: 10.1371/journal.pone.0210535.

Leduc V., Jasmin-Belanger S., Poirier J. APOE and cholesterol homeostasis in Alzheimer's disease. Trends Mol. Med. 16:469-477. 2010. doi: 10.1016/j.molmed.2010.07.008.

Kojro E., Gimpl G., Lammich S., Marz W., Fahrenholz F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the α-secretase ADAM 10. Proc. Natl. Acad. Sci. USA. 98:5815-5820. 2001.

Igbavboa U., Sun G.Y., Weisman G.A., He Y., Wood W.G. Amyloid β-protein stimulates trafficking of cholesterol and caveolin-1 from the plasma membrane to the Golgi complex in mouse primary astrocytes. Neuroscience. 162:328-338. 2009. doi: 10.1016/j.neuroscience.2009.04.049.

Brown A.M., Bevan D.R. Influence of sequence and lipid type on membrane perturbation by human and rat amyloid β-peptide (1-42). Arch. Biochem. Biophys. 614:1-13. 2017. doi: 10.1016/j.abb.2016.11.006.

Koudinov A.R., Koudinova N.V., Berezov T.T. Alzheimer's peptides Aβ1-40 and Aβ1-28 inhibit the plasma cholesterol esterification rate. Biochem. Mol. Biol. Int. 38:747-752. 1996. PMID: 8728104.

Grosgen S., Grimm M.O., Friess P., Hartmann T. Role of amyloid β in lipid homeostasis. Biochim. Biophys. Acta 1801:966-974. 2010. doi: 10.1016/j.bbalip.2010.05.002.

McFarlane O., Kędziora-Kornatowska K. Cholesterol and Dementia: A Long and Complicated Relationship. Curr. Aging Sci. 2019 Sep 17. doi: 10.2174/1874609812666190917155400. [Epub ahead of print].

Jeong A., Suazo K.F., Wood W.G., Distefano M.D. Isoprenoids and protein prenylation: implications in the pathogenesis and therapeutic intervention of Alzheimer's disease. Crit. Rev. Biochem. Mol. Biol. 53:279-310. 2018. doi: 10.1080/10409238.2018.1458070.

Petek B., Villa-Lopez M., Loera-Valencia R., Gerenu G., Winblad B., Kramberger M.G., Ismail M., Eriksdotter M., Garcia-Ptacek S. Connecting the brain cholesterol and renin-angiotensin systems: potential role of statins and RAS-modifying medications in dementia. J. Intern. Med. 284:620-642. 2018. doi: 10.1111/joim.12838.

Zandl-Lang M., Fanaee-Danesh E., Sun Y., Albrecher N.M., Gali C.C., Čančar I., Kober A., Tam-Amersdorfer C., Stracke A., Storck S.M., Saeed A., Stefulj J., Pietrzik C.U., Wilson M.R., Björkhem I., Panzenboeck U. Regulatory effects of simvastatin and apoJ on APP processing and amyloid-β clearance in blood-brain barrier endothelial cells. Biochim. Biophys. Acta Mol. Cell Biol. Lipids. 1863:40-60. 2018. doi: 10.1016/j.bbalip.2017.09.008.

Shinohara M., Sato N., Kurinami H., Takeuchi D., Takeda S., Shimamura M., Yamashita T., Uchiyama Y., Rakugi H., Morishita R. Reduction of brain Aβ by fluvastatin, an HMG-CoA reductase inhibitor, through increase in degradation of APP-CTFs and Aβ clearance. J. Biol. Chem. 285:22091-22102. 2010. doi: 10.1074/jbc.M110.102277.

Etcheberrigaray R., Tan M., Dewachter I., Kuipéri C., Van der Auwera I., Wera S., Qiao L., Bank B., Nelson T.J., Kozikowski A.P., Van Leuven F., Alkon D.L. Therapeutic effects of PKC activators in Alzheimer’s disease transgenic mice. Proc. Natl. Acad. Sci. USA. 101: 11141–11146. 2004. doi: 10.1073/pnas.0403921101.

Sun M.K., Alkon D.L. Dual effects of bryostatin‐1 on spatial memory and depression. Eur. J. Pharmacol. 512:43–51. 2005. doi: 10.1016/j.ejphar.2005.02.028.

Crestini A., Piscopo P., Iazeolla M., Albani D., Rivabene R., Forloni G., Confaloni A. Rosuvastatin and thapsigargin modulate γ-secretase gene expression and APP processing in a human neuroglioma model. J. Mol. Neurosci. 43:461-469. 2011.doi: 10.1007/s12031-010-9465-3.

Huang M., Hu M., Song Q., Song H., Huang J., Gu X., Wang X., Chen J., Kang T., Feng X., Jiang D., Zheng G., Chen H., Gao X. GM1-Modified Lipoprotein-like Nanoparticle: Multifunctional Nanoplatform for the Combination Therapy of Alzheimer's Disease. ACS Nano. 9:10801-10816. 2015. doi: 10.1021/acsnano.5b03124

Frisardi V., Panza F., Seripa D., Farooqui T., Farooqui A.A. Glycerophospholipids and glycerophospholipid-derived lipid mediators: a complex meshwork in Alzheimer's disease pathology. Prog. Lipid Res. 50:313-30. 2011. doi: 10.1016/j.plipres.2011.06.001

Díaz M., Fabelo N., Martín V., Ferrer I., Gómez T., Marín R. Biophysical alterations in lipid rafts from human cerebral cortex associate with increased BACE1/AβPP interaction in early stages of Alzheimer's disease. J. Alzheimers Dis. 43:1185-1198. 2015. doi: 10.3233/JAD-141146

Grimm M.O.W., Michaelson D.M., Hartmann T. Omega-3 fatty acids, lipids, and apoE lipidation in Alzheimer's disease: a rationale for multi-nutrient dementia prevention. J. Lipid Res. 58:2083-2101. 2017. doi: 10.1194/jlr.R076331

Zhang X.L., Zhao N., Xu B., Chen X.H., Li T.J. Treadmill exercise inhibits amyloid-β generation in the hippocampus of APP/PS1 transgenic mice by reducing cholesterol-mediated lipid raft formation. Neuroreport. 307:498-503. 2019. doi: 10.1097/WNR.0000000000001230

Zhang L., Han X., Wang X. Is the clinical lipidomics a potential goldmine? Cell. Biol. Toxicol. 34:421-423. 2018. doi: 10.1007/s10565-018-9441-1

Hardy J., Escott-Price V. Genes, pathways and risk prediction in Alzheimer's disease. Hum. Mol. Genet. 28:235-240. 2019. doi: 10.1093/hmg/ddz163