APOE from astrocytes restores Alzheimer's Aβ-pathology and DAM-like responses in APOE deficient microglia.

Publisher: EMBO Press Country of Publication: Germany NLM ID: 101487380 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1757-4684 (Electronic) Linking ISSN: 17574676 NLM ISO Abbreviation: EMBO Mol Med Subsets: MEDLINE

Publication: 2024- : Heidelberg : EMBO Press
Original Publication: Chichester, West Sussex : Wiley-Blackwell

Astrocytes*/metabolism ; Astrocytes*/pathology ; Microglia*/metabolism ; Microglia*/pathology ; Alzheimer Disease*/pathology ; Alzheimer Disease*/metabolism ; Alzheimer Disease*/genetics ; Apolipoproteins E*/genetics ; Apolipoproteins E*/metabolism ; Apolipoproteins E*/deficiency ; Amyloid beta-Peptides*/metabolism; Animals ; Mice ; Humans ; Plaque, Amyloid/metabolism ; Plaque, Amyloid/pathology ; Disease Models, Animal ; Apolipoprotein E4/metabolism ; Apolipoprotein E4/genetics ; Mice, Transgenic

The major genetic risk factor for Alzheimer's disease (AD), APOE4, accelerates beta-amyloid (Aβ) plaque formation, but whether this is caused by APOE expressed in microglia or astrocytes is debated. We express here the human APOE isoforms in astrocytes in an Apoe-deficient AD mouse model. This is not only sufficient to restore the amyloid plaque pathology but also induces the characteristic transcriptional pathological responses in Apoe-deficient microglia surrounding the plaques. We find that both APOE4 and the protective APOE2 from astrocytes increase fibrillar plaque deposition, but differentially affect soluble Aβ aggregates. Microglia and astrocytes show specific alterations in function of APOE genotype expressed in astrocytes. Our experiments indicate a central role of the astrocytes in APOE mediated amyloid plaque pathology and in the induction of associated microglia responses.
Competing Interests: Disclosure and competing interests statement. BDS is or has been a consultant for Eli Lilly, Biogen, Janssen Pharmaceutica, Eisai, AbbVie and other companies. BDS is an Editorial Board Member for EMBO Molecular Medicine. BDS is also a scientific founder of Augustine Therapeutics and a scientific founder and stockholder of Muna Therapeutics.
(© 2024. The Author(s).)

Nat Genet. 2022 Apr;54(4):412-436. (PMID: 35379992)
Neurology. 2009 Apr 28;72(17):1495-503. (PMID: 19398704)
Neuroscience. 1995 Dec;69(3):757-61. (PMID: 8596645)
J Neurosci. 2017 Apr 12;37(15):4023-4031. (PMID: 28275161)
J Neurosci. 2004 Mar 10;24(10):2527-34. (PMID: 15014128)
Ann Neurol. 2009 Jun;65(6):650-7. (PMID: 19557866)
Ann Neurol. 2000 Jun;47(6):739-47. (PMID: 10852539)
Nat Immunol. 2023 Nov;24(11):1854-1866. (PMID: 37857825)
Elife. 2018 Oct 30;7:. (PMID: 30375977)
JAMA Neurol. 2013 Feb;70(2):223-8. (PMID: 23407718)
J Alzheimers Dis. 2015;46(3):611-29. (PMID: 25835425)
Cell. 2017 Jun 15;169(7):1276-1290.e17. (PMID: 28602351)
Acta Neuropathol Commun. 2016 Oct 27;4(1):111. (PMID: 27788676)
Sci Rep. 2015 Nov 25;5:16923. (PMID: 26603754)
J Neurosci. 2009 May 27;29(21):6771-9. (PMID: 19474305)
J Neurosci. 2014 Sep 3;34(36):11929-47. (PMID: 25186741)
J Clin Invest. 1985 Oct;76(4):1501-13. (PMID: 3932467)
Nat Commun. 2020 Oct 8;11(1):5073. (PMID: 33033238)
J Biol Chem. 1999 Nov 5;274(45):32301-8. (PMID: 10542270)
Nature. 2020 May;581(7806):71-76. (PMID: 32376954)
J Alzheimers Dis. 2016;51(3):915-27. (PMID: 26923027)
J Biol Chem. 2002 Jun 14;277(24):21821-8. (PMID: 11912196)
BMC Neurol. 2008 Apr 16;8:9. (PMID: 18416843)
Neurology. 2010 Nov 30;75(22):1976-81. (PMID: 20980669)
Neuron. 2018 Jun 27;98(6):1141-1154.e7. (PMID: 29861287)
JAMA. 1997 Oct 22-29;278(16):1349-56. (PMID: 9343467)
Nat Biotechnol. 2010 Apr;28(4):348-53. (PMID: 20231818)
J Neurosci. 2008 Nov 5;28(45):11445-53. (PMID: 18987181)
Neurology. 2012 Jan 24;78(4):232-40. (PMID: 22189452)
Cell Death Dis. 2020 Jan 6;11(1):11. (PMID: 31907354)
Acta Neuropathol. 2018 Jul;136(1):19-40. (PMID: 29687257)
Science. 2022 Nov 4;378(6619):eadc9020. (PMID: 36378959)
Neurology. 2009 Mar 3;72(9):829-34. (PMID: 19255410)
Proc Natl Acad Sci U S A. 2013 May 7;110(19):E1807-16. (PMID: 23620513)
Gigascience. 2018 Jul 1;7(7):. (PMID: 30010766)
Cell. 2018 Aug 9;174(4):999-1014.e22. (PMID: 30096314)
Cell Rep. 2019 Apr 23;27(4):1293-1306.e6. (PMID: 31018141)
Nat Neurosci. 2021 Oct;24(10):1475-1487. (PMID: 34413515)
Glia. 2011 Nov;59(11):1567-78. (PMID: 21850709)
Neurobiol Aging. 2013 Jan;34(1):1-12. (PMID: 22633529)
Nature. 2017 Sep 28;549(7673):523-527. (PMID: 28959956)
J Magn Reson Imaging. 2017 Jan;45(1):103-117. (PMID: 27345946)
Nat Commun. 2020 Mar 5;11(1):1220. (PMID: 32139688)
J Neurosci. 2010 Oct 13;30(41):13707-17. (PMID: 20943911)
Nat Neurosci. 2023 Jul;26(7):1196-1207. (PMID: 37291336)
Arthritis Res Ther. 2008;10(1):201. (PMID: 18226189)
Ann Neurol. 2022 Jun;91(6):847-852. (PMID: 35285073)
Cell Rep. 2019 Jan 8;26(2):394-406.e5. (PMID: 30625322)
J Neuroinflammation. 2021 Mar 17;18(1):73. (PMID: 33731156)
Acta Neuropathol Commun. 2019 May 21;7(1):82. (PMID: 31113487)
Cell. 2022 Jun 23;185(13):2213-2233.e25. (PMID: 35750033)
Arch Neurol. 2007 Aug;64(8):1193-6. (PMID: 17698712)
Lancet. 1994 Jun 4;343(8910):1432-3. (PMID: 7910910)
Neurology. 2017 Feb 7;88(6):569-576. (PMID: 28062720)
Nucleic Acids Res. 2023 Jul 5;51(W1):W207-W212. (PMID: 37144459)
Acta Neuropathol. 2000 Oct;100(4):356-64. (PMID: 10985692)
Front Mol Neurosci. 2023 Apr 04;16:1149683. (PMID: 37082656)
Nat Aging. 2023 Mar;3(3):275-296. (PMID: 37118426)
Cell Rep. 2022 Aug 16;40(7):111200. (PMID: 35977506)
Cell. 2020 Aug 20;182(4):976-991.e19. (PMID: 32702314)
Neurology. 1997 Jan;48(1):139-47. (PMID: 9008509)
J Alzheimers Dis. 2015;45(1):253-68. (PMID: 25524955)
Neuron. 2014 Apr 16;82(2):380-97. (PMID: 24742461)
Neuron. 2021 May 19;109(10):1657-1674.e7. (PMID: 33831349)
Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7437-41. (PMID: 1502155)
Alzheimers Dement. 2023 Jun;19(6):2239-2252. (PMID: 36448627)
Nat Genet. 2007 Dec;39(12):1440-2. (PMID: 18026100)
PeerJ. 2014 Jun 19;2:e453. (PMID: 25024921)
Nat Aging. 2021 Oct;1(10):919-931. (PMID: 36199750)
Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15233-8. (PMID: 10611368)
Immunity. 2017 Sep 19;47(3):566-581.e9. (PMID: 28930663)
J Neurosci. 2009 Jun 24;29(25):8075-86. (PMID: 19553447)
Cell. 2021 Jun 24;184(13):3573-3587.e29. (PMID: 34062119)
Am J Pathol. 2010 Aug;177(2):563-9. (PMID: 20595630)
J Cell Physiol. 2019 May;234(5):5379-5389. (PMID: 30350856)
Neuron. 2017 Aug 2;95(3):531-549.e9. (PMID: 28712653)
Science. 1993 Aug 13;261(5123):921-3. (PMID: 8346443)
J Neurosci. 2012 May 2;32(18):6391-410. (PMID: 22553043)
J Neurosci. 2008 Jan 2;28(1):264-78. (PMID: 18171944)
J Vis Exp. 2014 Sep 15;(91):51863. (PMID: 25286085)
Neuroscience. 2010 Dec 29;171(4):1265-72. (PMID: 20951774)
Nat Neurosci. 2019 Dec;22(12):2111-2116. (PMID: 31659342)
Cell. 2024 Jan 18;187(2):428-445.e20. (PMID: 38086389)
J Biol Chem. 2004 Apr 16;279(16):15841-9. (PMID: 14752115)
ACS Chem Neurosci. 2012 Nov 21;3(11):832-44. (PMID: 23173065)
Endocrinology. 1998 Jan;139(1):65-71. (PMID: 9421399)
Nat Methods. 2012 Jun 28;9(7):676-82. (PMID: 22743772)
Lancet Neurol. 2018 Jan;17(1):64-74. (PMID: 29263008)
J Alzheimers Dis. 2019;70(3):861-875. (PMID: 31306119)
Stem Cell Res. 2015 Nov;15(3):522-529. (PMID: 26451648)
Neurobiol Dis. 2002 Apr;9(3):305-18. (PMID: 11950276)
Front Neurosci. 2017 Dec 12;11:702. (PMID: 29311783)
Mol Neurodegener. 2021 Jan 31;16(1):5. (PMID: 33517893)
J Exp Med. 2018 Apr 2;215(4):1047-1058. (PMID: 29483128)
Acta Neuropathol. 2014;127(6):811-24. (PMID: 24659241)
Neurobiol Aging. 2016 Apr;40:68-77. (PMID: 26973105)
Mol Psychiatry. 2014 Nov;19(11):1243-50. (PMID: 24492349)
Nat Immunol. 2023 Nov;24(11):1839-1853. (PMID: 37749326)
Glia. 2022 Feb;70(2):287-302. (PMID: 34643971)
Free Radic Biol Med. 2002 Jun 1;32(11):1071-5. (PMID: 12031891)
Nat Med. 2019 Nov;25(11):1680-1683. (PMID: 31686034)
Mol Neurodegener. 2019 Oct 17;14(1):37. (PMID: 31623648)
Nat Commun. 2022 Sep 20;13(1):5512. (PMID: 36127374)
Nat Immunol. 2021 May;22(5):586-594. (PMID: 33859405)
Brain. 2012 Jul;135(Pt 7):2155-68. (PMID: 22637583)
J Neuroinflammation. 2014 Jun 19;11:111. (PMID: 24948358)
J Neurosci. 2011 Dec 7;31(49):18007-12. (PMID: 22159114)
Hum Mol Genet. 2014 Dec 1;23(23):6139-46. (PMID: 24973356)
J Neurosci. 2005 Mar 16;25(11):2803-10. (PMID: 15772340)
Neuroimage. 2013 Sep;78:474-80. (PMID: 23624169)
Neurology. 2016 Oct 18;87(16):1696-1703. (PMID: 27683850)
J Neurosci. 2006 May 10;26(19):4985-94. (PMID: 16687490)
Stem Cell Reports. 2018 Sep 11;11(3):770-783. (PMID: 30174314)
Neurosci Lett. 2003 Mar 27;339(3):183-6. (PMID: 12633883)
Mol Neurodegener. 2023 Mar 16;18(1):17. (PMID: 36922879)
Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9649-53. (PMID: 8415756)
Neurobiol Aging. 2016 Aug;44:159-172. (PMID: 27318144)
EMBO J. 2020 Jul 1;39(13):e104163. (PMID: 32484994)
J Neurosci. 2009 Dec 2;29(48):15317-22. (PMID: 19955384)
N Engl J Med. 1995 Nov 9;333(19):1242-7. (PMID: 7566000)
Alzheimers Dement. 2018 Feb;14(2):230-242. (PMID: 28945989)
Am J Pathol. 1994 Nov;145(5):1030-5. (PMID: 7977635)
Lancet Neurol. 2018 Sep;17(9):773-781. (PMID: 30093249)
Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20324-9. (PMID: 19910533)
Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1211-6. (PMID: 15657137)
Nature. 2024 Mar;627(8003):358-366. (PMID: 38418885)
Cell. 2019 May 2;177(4):1022-1034.e6. (PMID: 31051098)
Brain. 2016 Apr;139(Pt 4):1265-81. (PMID: 26921617)
Sci Transl Med. 2013 Nov 20;5(212):212ra161. (PMID: 24259049)
Mov Disord. 2018 Feb;33(2):289-297. (PMID: 29168904)
Glia. 2021 Jun;69(6):1478-1493. (PMID: 33556209)
J Neurosci. 2002 Jan 1;22(1):183-92. (PMID: 11756501)
Int J Biomed Imaging. 2022 Apr 20;2022:5336373. (PMID: 35496640)
Nat Methods. 2021 Jan;18(1):100-106. (PMID: 33318659)
Neurology. 2005 Dec 27;65(12):1888-93. (PMID: 16380608)
Dement Geriatr Cogn Disord. 2006;22(1):15-9. (PMID: 16645276)
Proc Natl Acad Sci U S A. 2018 Feb 20;115(8):E1896-E1905. (PMID: 29437957)
Nucleic Acids Res. 2007;35(19):e128. (PMID: 17897965)
Bioinformatics. 2017 Apr 15;33(8):1179-1186. (PMID: 28088763)
Proc Natl Acad Sci U S A. 2018 Jul 10;115(28):E6640-E6649. (PMID: 29946028)
Nat Neurosci. 2014 May;17(5):661-3. (PMID: 24728269)
Ann Neurol. 2015 Jun;77(6):917-29. (PMID: 25623662)
J Biol Chem. 2005 Dec 30;280(52):43236-42. (PMID: 16207708)
Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886)
Nat Genet. 1994 Jun;7(2):180-4. (PMID: 7920638)
Neurobiol Aging. 2005 Mar;26(3):363-72. (PMID: 15639315)
J Neurosci. 2012 Apr 4;32(14):4803-11. (PMID: 22492035)
Nature. 2012 May 16;485(7399):512-6. (PMID: 22622580)
Cell. 2016 Feb 11;164(4):603-15. (PMID: 26871627)
Sci Adv. 2022 Sep 30;8(39):eabq2423. (PMID: 36179025)
JAMA Neurol. 2013 Aug;70(8):972-80. (PMID: 23779114)
Nature. 1994 Nov 3;372(6501):92-4. (PMID: 7969426)
J Clin Invest. 2008 Dec;118(12):4002-13. (PMID: 19033669)
J Biol Chem. 2005 Dec 30;280(52):43224-35. (PMID: 16207713)
Mol Psychiatry. 2022 Nov;27(11):4800-4808. (PMID: 36071110)
Arch Neurol. 2006 Feb;63(2):189-93. (PMID: 16476806)
Nature. 2022 Nov;611(7937):769-779. (PMID: 36385529)
Neurosci Lett. 1994 Jul 4;175(1-2):46-8. (PMID: 7970208)
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2892-7. (PMID: 10694577)
Nat Neurosci. 2024 May;27(5):886-900. (PMID: 38539015)
Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81. (PMID: 8446617)
J Neurosci. 2014 Oct 15;34(42):14069-78. (PMID: 25319703)
Elife. 2021 Oct 07;10:. (PMID: 34617884)
J Biol Chem. 2012 Dec 7;287(50):41774-86. (PMID: 23060451)
Ann Neurol. 2012 Oct;72(4):587-98. (PMID: 23037886)
Front Neurol. 2021 Oct 20;12:735036. (PMID: 34744974)
J Neurosci. 2016 Sep 28;36(39):10141-50. (PMID: 27683909)
J Clin Invest. 2018 May 1;128(5):2144-2155. (PMID: 29600961)
EMBO Rep. 2018 Nov;19(11):. (PMID: 30206190)
Nat Commun. 2024 Jun 1;15(1):4695. (PMID: 38824138)
J Neuroinflammation. 2021 Apr 3;18(1):86. (PMID: 33812385)
Sci Rep. 2019 Aug 29;9(1):12579. (PMID: 31467325)
Neuron. 2017 Dec 6;96(5):1013-1023.e4. (PMID: 29216448)
Mol Neurodegener. 2022 Feb 2;17(1):13. (PMID: 35109920)
Mol Neurodegener. 2016 Feb 03;11:14. (PMID: 26842216)
Neurobiol Aging. 2004 Sep;25(8):1033-43. (PMID: 15212828)
J Neurochem. 2019 Aug;150(4):420-440. (PMID: 31222732)
Nature. 2020 Apr;580(7803):381-385. (PMID: 32296178)
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6412-7. (PMID: 17404210)
Sci Transl Med. 2021 Feb 17;13(581):. (PMID: 33597265)
Bioinformatics. 2013 Jun 1;29(11):1448-54. (PMID: 23603332)
Nat Commun. 2017 Jan 16;8:14049. (PMID: 28091601)
Neurobiol Aging. 2009 Sep;30(9):1350-60. (PMID: 18155324)
Bioinformatics. 2010 Mar 15;26(6):841-2. (PMID: 20110278)
Sci Transl Med. 2011 Jun 29;3(89):89ra57. (PMID: 21715678)
Nat Rev Drug Discov. 2011 Dec 01;10(12):945-63. (PMID: 22129992)
Development. 2004 Nov;131(22):5539-50. (PMID: 15496443)
Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):2018-22. (PMID: 19164761)
Nat Aging. 2021 Jun;1(6):506-520. (PMID: 35291561)
Brain Commun. 2021 Jul 02;3(3):fcab147. (PMID: 34396107)
Nat Neurosci. 2022 Mar;25(3):306-316. (PMID: 35260865)
Biochem J. 1995 Mar 1;306 ( Pt 2):599-604. (PMID: 7534068)
Nat Neurosci. 2020 Jun;23(6):701-706. (PMID: 32341542)
Neuron. 2021 Aug 4;109(15):2413-2426.e7. (PMID: 34157306)
Neuron. 2017 Dec 6;96(5):1024-1032.e3. (PMID: 29216449)
JAMA Neurol. 2018 Nov 1;75(11):1347-1354. (PMID: 30422173)
Nat Commun. 2020 Feb 3;11(1):667. (PMID: 32015339)

MR/Y014847/1 UK Research and Innovation (UKRI); ERC-834682 EC | European Research Council (ERC); MCIN/AEI/10.13039/501100011033 Ministerio de Ciencia e Innovación (MCIN); PIBA-2020-1-0030 Basque government, Spain

Keywords: APOE; Alzheimer’s Disease; Astrocytes; Microglia; β-amyloid Pathology

0 (Apolipoproteins E)
0 (Amyloid beta-Peptides)
0 (Apolipoprotein E4)

Date Created: 20241111 Date Completed: 20241209 Latest Revision: 20241212

20241212

PMC11628604

10.1038/s44321-024-00162-7

39528861