Sphingolipid-Enriched Extracellular Vesicles and Alzheimer's Disease: A Decade of Research.
Extracellular vesicles (EVs), particularly exosomes, have emerged in the last 10 years as a new player in the progression of Alzheimer's disease (AD) with high potential for being useful as a diagnostic and treatment tool. Exosomes and other EVs are enriched with the sphingolipid ceramide as well as other more complex glycosphingolipids such as gangliosides. At least a subpopulation of exosomes requires neutral sphingomyelinase activity for their biogenesis and secretion. As ceramide is often elevated in AD, exosome secretion may be affected as well. Here, we review the available data showing that exosomes regulate the aggregation and clearance of amyloid-beta (Aβ) and discuss the differences in data from laboratories regarding Aβ binding, induction of aggregation, and glial clearance. We also summarize available data on the role of exosomes in extracellular tau propagation, AD-related exosomal mRNA/miRNA cargo, and the use of exosomes as biomarker and gene therapy vehicles for diagnosis and potential treatment.
Department of Neuroscience and Regenerative Medicine, The Medical College of Georgia, Augusta University, Augusta, GA, USA.
Michael B
MB
Dinkins
Department of Neuroscience and Regenerative Medicine, The Medical College of Georgia, Augusta University, Augusta, GA, USA.
Guanghu
G
Wang
Department of Neuroscience and Regenerative Medicine, The Medical College of Georgia, Augusta University, Augusta, GA, USA.
Erhard
E
Bieberich
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000067128:Extracellular Vesicles / Q000378:metabolism*; D006801:Humans; D013107:Sphingolipids / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D013107:Sphingolipids
Alzheimer’s disease; amyloid; biomarker; ceramide; exosome; miRNA; sphingomyelinase; tau; vesicle
EMBO J. 2008 Jan 9;27(1):224-33
18059472
J Hered. 1981 Nov-Dec;72(6):440-1
6801109
J Neurosci. 2011 Sep 14;31(37):13110-7
21917794
Am J Pathol. 2007 Mar;170(3):921-9
17322377
Proteomics. 2013 May;13(10-11):1554-71
23401200
Alzheimers Dement. 2016 Nov;12(11):1125-1131
27234211
J Alzheimers Dis. 2014;40 Suppl 1:S47-70
24718102
Neurobiol Aging. 2014 Aug;35(8):1792-800
24650793
Neuron. 2015 Jan 21;85(2):296-302
25611508
J Biol Chem. 2012 Jun 15;287(25):21384-95
22532571
PLoS One. 2015 Oct 01;10(10):e0139233
26426747
J Biol Chem. 2001 Jul 6;276(27):24985-90
11342534
J Alzheimers Dis. 2010;19(2):647-64
20110609
Front Immunol. 2016 Jan 29;7:17
26858720
FASEB J. 2013 Dec;27(12):5141-50
24014820
Science. 2001 May 25;292(5521):1550-2
11375493
Exp Gerontol. 2013 Jul;48(7):626-33
23283304
J Biol Chem. 2010 Nov 26;285(48):37405-14
20876579
Biochem Soc Trans. 2013 Feb 1;41(1):241-4
23356290
J Biol Chem. 1998 Jun 5;273(23):14550-9
9603970
Arch Biochem Biophys. 2001 Apr 15;388(2):225-30
11368158
Front Cell Neurosci. 2014 Apr 23;8:113
24795568
Ann Neurol. 2014 Dec;76(6):813-25
25087695
J Biol Chem. 2012 Feb 3;287(6):3842-9
22057275
Mol Brain. 2013 Nov 13;6:47
24284042
Nat Neurosci. 2015 Nov;18(11):1584-93
26436904
Science. 2008 Feb 29;319(5867):1244-7
18309083
Nat Cell Biol. 2009 Jul;11(7):909-13
19503072
Alzheimers Res Ther. 2014 Jul 03;6(4):37
25024750
J Extracell Vesicles. 2015 Nov 11;4:28680
26563734
Biochem Pharmacol. 2012 Jun 1;83(11):1484-94
22230477
Brain Res. 2016 Sep 1;1646:139-151
27235866
Nat Biotechnol. 2011 Apr;29(4):341-5
21423189
J Extracell Vesicles. 2014 Dec 22;3:26913
25536934
J Biol Chem. 2002 Jun 21;277(25):22768-80
11912199
J Neurol Sci. 2016 Jan 15;360:141-52
26723991
Glia. 2008 Mar;56(4):449-56
18205190
FEBS Lett. 2012 Jan 2;586(1):47-54
22138183
Neurology. 2015 Jul 7;85(1):40-7
26062630
J Neurochem. 2008 Apr;105(1):217-24
18021298
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4162-7
12634421
Curr Opin Cell Biol. 2014 Aug;29:116-25
24959705
Mol Psychiatry. 2015 Oct;20(10):1188-96
25349172
Cell Mol Neurobiol. 2016 Apr;36(3):327-42
26983829
Cell Death Differ. 2014 Apr;21(4):582-93
24336048
Trends Cell Biol. 2015 Jun;25(6):364-72
25683921
J Neurosci. 2016 Aug 17;36(33):8653-67
27535912
Langmuir. 2015 Oct 27;31(42):11549-57
26474149
Biochim Biophys Acta. 2013 Jul;1831(7):1302-9
24046871
Neurobiol Dis. 2009 Feb;33(2):229-35
19026746
Alzheimers Dement. 2015 May;11(5):465-74
25200336
Biochem J. 2004 May 15;380(Pt 1):161-71
14965343
J Extracell Vesicles. 2012 Apr 16;1:
24009879
Proteomics. 2013 May;13(10-11):1624-36
23526769
J Biol Chem. 2007 Jun 22;282(25):18197-18205
17468104
Nat Neurosci. 2015 Jun;18(6):800-6
26007213
J Alzheimers Dis. 2010;19(1):79-95
20061628
Biochim Biophys Acta. 2014 Jan;1841(1):108-20
24140720
J Biol Chem. 2014 Aug 29;289(35):24488-98
25037226
Nat Genet. 2005 Aug;37(8):803-5
16025116
Nat Med. 1998 Aug;4(8):957-62
9701251
Nat Cell Biol. 2007 Jun;9(6):654-9
17486113
Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):14888-93
25267620
J Neurosci. 2006 Oct 4;26(40):10129-40
17021169
J Biol Chem. 2016 Jun 10;291(24):12445-12466
27030011
FEBS Lett. 2015 Jan 2;589(1):84-8
25436414
Alzheimers Dement. 2015 May;11(5):561-78
25443858
Science. 2008 Aug 29;321(5893):1221-4
18755980
J Biol Chem. 2002 Oct 25;277(43):41128-39
12154098
Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):E968-77
26858453
Clin Pharmacol Ther. 2015 Nov;98(5):469-71
26250900
FASEB J. 2015 Feb;29(2):589-96
25342129
J Extracell Vesicles. 2016 Feb 19;5:29975
26901056
Mol Biol Cell. 2015 Dec 1;26(24):4451-65
26446842
FASEB J. 2008 May;22(5):1469-78
18171695
Glia. 2016 Jun;64(6):952-62
26875818
Nat Rev Neurosci. 2008 Oct;9(10):768-78
18802446
EMBO J. 2009 Apr 22;28(8):1043-54
19300439
J Biol Chem. 2012 Mar 30;287(14):10977-89
22303002
J Pathol. 2007 Apr;211(5):582-590
17334982
Ann Clin Transl Neurol. 2015 Jul;2(7):769-73
26273689
J Biol Chem. 2013 Apr 12;288(15):10849-59
23439645
J Neurosci. 2003 Oct 1;23(26):8844-53
14523085
Cell Rep. 2015 Oct 6;13(1):43-51
26387950
Mol Med Rep. 2014 Nov;10(5):2395-400
25119742
Oncotarget. 2015 Nov 10;6(35):37043-53
26497684
Front Genet. 2012 Apr 20;3:56
22529849
Genomics Proteomics Bioinformatics. 2015 Feb;13(1):17-24
25724326
J Lipid Res. 2007 Apr;48(4):968-75
17210985
J Neurochem. 2016 Apr;137(1):88-100
26710111
J Biol Chem. 2005 Apr 8;280(14):13824-32
15671026
J Neurosci. 2004 May 19;24(20):4894-902
15152051
Alzheimers Dement. 2015 Jun;11(6):600-7.e1
25130657
Acta Neuropathol. 2015 Feb;129(2):207-20
25492702
Annu Rev Cell Dev Biol. 2014;30:255-89
25288114
Front Genet. 2013 Aug 08;4:150
23964286
J Proteomics. 2010 Sep 10;73(10):1907-20
20601276
Biochem J. 1991 Mar 1;274 ( Pt 2):381-6
1848755
Annu Rev Neurosci. 2011;34:185-204
21456963
Nat Rev Neurosci. 2011 Feb;12(2):65-72
21193853
J Extracell Vesicles. 2014 Sep 18;3:
25317274
J Biol Chem. 2012 Dec 14;287(51):43108-15
23129776
Alzheimers Dement (Amst). 2016 May 07;3:63-72
27408937
Swiss Med Wkly. 2015 Nov 12;145:w14204
26561744
Sci Rep. 2013;3:1197
23378928
Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11172-7
16837572
PLoS One. 2014 Jun 27;9(6):e100760
24971751
Traffic. 2009 Jul;10(7):925-37
19490536