title: Mint proteins are required for synaptic activity-dependent amyloid precursor protein (APP) trafficking and amyloid β generation.
abstract: Aberrant amyloid β (Aβ) production plays a causal role in Alzheimer disease pathogenesis. A major cellular pathway for Aβ generation is the activity-dependent endocytosis and proteolytic cleavage of the amyloid precursor protein (APP). However, the molecules controlling activity-dependent APP trafficking in neurons are less defined. Mints are adaptor proteins that directly interact with the endocytic sorting motif of APP and are functionally important in regulating APP endocytosis and Aβ production. We analyzed neuronal cultures from control and Mint knockout neurons that were treated with either glutamate or tetrodotoxin to stimulate an increase or decrease in neuronal activity, respectively. We found that neuronal activation by glutamate increased APP endocytosis, followed by elevated APP insertion into the cell surface, stabilizing APP at the plasma membrane. Conversely, suppression of neuronal activity by tetrodotoxin decreased APP endocytosis and insertion. Interestingly, we found that activity-dependent APP trafficking and Aβ generation were blocked in Mint knockout neurons. We showed that wild-type Mint1 can rescue APP internalization and insertion in Mint knockout neurons. In addition, we found that Mint overexpression increased excitatory synaptic activity and that APP was internalized predominantly to endosomes associated with APP processing. We demonstrated that presenilin 1 (PS1) endocytosis requires interaction with the PDZ domains of Mint1 and that this interaction facilitates activity-dependent colocalization of APP and PS1. These findings demonstrate that Mints are necessary for activity-induced APP and PS1 trafficking and provide insight into the cellular fate of APP in endocytic pathways essential for Aβ production.
authors.affiliation: From the Department of Biology, Boston University, Boston, Massachusetts 02215.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Sullivan
authors.affiliation: From the Department of Biology, Boston University, Boston, Massachusetts 02215.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Dillon
authors.affiliation: From the Department of Biology, Boston University, Boston, Massachusetts 02215.
authors.forename: Josefa M
authors.initials: JM
authors.lastname: Sullivan
authors.affiliation: From the Department of Biology, Boston University, Boston, Massachusetts 02215 aho1@bu.edu.
authors.forename: Angela
authors.initials: A
authors.lastname: Ho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D053764:Presenilin-1 / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: C079091:APBA1 protein, human; C491636:APBA2 protein, human; C117536:APBA3 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D015820:Cadherins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D026941:Sodium Channel Blockers; C580804:presenilin 1, mouse; D013779:Tetrodotoxin
keywords: Adaptor Protein; Alzheimer Disease; Amyloid; Amyloid Precursor Protein (APP); Mint/X11; Synaptic Activity; Trafficking
references.citation: Nature. 2013 Aug 1;500(7460):45-50
references.pmid: 23883936
references.citation: J Neurosci Res. 2007 Sep;85(12):2580-90
references.pmid: 17335075
references.citation: J Clin Invest. 2005 Nov;115(11):3285-90
references.pmid: 16239972
references.citation: Epilepsy Res. 2003 Nov;57(1):49-57
references.pmid: 14706732
references.citation: J Neurosci. 2012 Oct 3;32(40):13906-16
references.pmid: 23035100
references.citation: Neuroscience. 2006;138(2):511-22
references.pmid: 16413130
references.citation: Neuron. 2003 Mar 27;37(6):925-37
references.pmid: 12670422
references.citation: Epilepsia. 2006 May;47(5):867-72
references.pmid: 16686651
references.citation: J Neurosci. 2008 Dec 31;28(53):14392-400
references.pmid: 19118172
references.citation: J Biol Chem. 1996 Apr 19;271(16):9390-7
references.pmid: 8621605
references.citation: Nat Struct Mol Biol. 2005 Aug;12(8):722-8
references.pmid: 16007100
references.citation: Neuron. 2006 Dec 7;52(5):831-43
references.pmid: 17145504
references.citation: J Biol Chem. 1996 Apr 12;271(15):9100-7
references.pmid: 8621560
references.citation: J Cell Biol. 1995 Feb;128(4):537-47
references.pmid: 7860629
references.citation: J Biol Chem. 1994 Jul 1;269(26):17386-9
references.pmid: 8021238
references.citation: Neurotoxicology. 2011 Dec;32(6):751-9
references.pmid: 21798282
references.citation: PLoS One. 2011 Apr 27;6(4):e18754
references.pmid: 21556148
references.citation: J Biol Chem. 1994 Jul 1;269(26):17741-8
references.pmid: 8021287
references.citation: Proc Natl Acad Sci U S A. 2013 May 7;110(19):7904-9
references.pmid: 23610434
references.citation: Neuron. 2013 Aug 7;79(3):447-60
references.pmid: 23931995
references.citation: J Biol Chem. 2000 Oct 27;275(43):33729-37
references.pmid: 10924510
references.citation: J Neurosci. 2009 Apr 8;29(14):4442-60
references.pmid: 19357271
references.citation: J Neurosci. 2012 Jul 11;32(28):9613-25
references.pmid: 22787047
references.citation: Cell. 2011 Oct 28;147(3):615-28
references.pmid: 22036569
references.citation: J Neurosci. 2007 Mar 14;27(11):2866-75
references.pmid: 17360908
references.citation: J Neurosci. 2013 May 8;33(19):8575-86
references.pmid: 23658195
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1409-14
references.pmid: 12547917
references.citation: J Biol Chem. 1997 Dec 12;272(50):31459-64
references.pmid: 9395480
references.citation: J Neurosci. 2007 Jul 18;27(29):7817-26
references.pmid: 17634375
references.citation: Neuron. 2008 Apr 10;58(1):42-51
references.pmid: 18400162
references.citation: Eur J Neurosci. 1999 Jun;11(6):1988-94
references.pmid: 10336668
references.citation: Mol Cell Biol. 1996 Nov;16(11):6229-41
references.pmid: 8887653
references.citation: Neuron. 2005 Dec 22;48(6):913-22
references.pmid: 16364896
references.citation: J Neurosci. 2006 Dec 13;26(50):13089-101
references.pmid: 17167098
references.citation: J Neurosci. 2002 Sep 1;22(17):7340-51
references.pmid: 12196555
references.citation: Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3802-7
references.pmid: 22355143
references.citation: Neuroreport. 2000 Nov 9;11(16):3607-10
references.pmid: 11095528
references.citation: Curr Opin Cell Biol. 2007 Apr;19(2):112-6
references.pmid: 17317137