Tyr682 in the Aβ-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance
Corresponding Author
Carmela Matrone
CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143 Italy
Department of Medical Biochemistry, University of Aarhus, 8000 Aarhus C, Denmark
These authors contributed equally to this work.Correspondence
Carmela Matrone, Department of Medical Biochemistry, University of Aarhus, 8000 Aarhus C, Denmark. Tel.: +45 87167821; fax: +45 86131160; e-mail: [email protected] or Luciano D'Adamio, Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, New York, NY 10461, USA. Tel.: +1 718 430 3244; fax: +1 718 430 8711; e-mail: [email protected]
Search for more papers by this authorSiro Luvisetto
CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143 Italy
These authors contributed equally to this work.Search for more papers by this authorLuca R. La Rosa
CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143 Italy
Search for more papers by this authorRobert Tamayev
Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, NY, 10461 USA
Search for more papers by this authorAnnabella Pignataro
CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143 Italy
Santa Lucia Foundation, Experimental Neurology Unit, Rome, 00143 Italy
Search for more papers by this authorNadia Canu
CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143 Italy
Department of Systems Medicine, University of Tor Vergata, Rome, 00133 Italy
Search for more papers by this authorLi Yang
Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030 USA
Search for more papers by this authorAlessia P. M. Barbagallo
Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, NY, 10461 USA
Search for more papers by this authorFabrizio Biundo
Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, NY, 10461 USA
Search for more papers by this authorFranco Lombino
Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, NY, 10461 USA
Search for more papers by this authorHui Zheng
Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030 USA
Search for more papers by this authorMartine Ammassari-Teule
CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143 Italy
Santa Lucia Foundation, Experimental Neurology Unit, Rome, 00143 Italy
Search for more papers by this authorCorresponding Author
Luciano D'Adamio
Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, NY, 10461 USA
Correspondence
Carmela Matrone, Department of Medical Biochemistry, University of Aarhus, 8000 Aarhus C, Denmark. Tel.: +45 87167821; fax: +45 86131160; e-mail: [email protected] or Luciano D'Adamio, Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, New York, NY 10461, USA. Tel.: +1 718 430 3244; fax: +1 718 430 8711; e-mail: [email protected]
Search for more papers by this authorCorresponding Author
Carmela Matrone
CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143 Italy
Department of Medical Biochemistry, University of Aarhus, 8000 Aarhus C, Denmark
These authors contributed equally to this work.Correspondence
Carmela Matrone, Department of Medical Biochemistry, University of Aarhus, 8000 Aarhus C, Denmark. Tel.: +45 87167821; fax: +45 86131160; e-mail: [email protected] or Luciano D'Adamio, Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, New York, NY 10461, USA. Tel.: +1 718 430 3244; fax: +1 718 430 8711; e-mail: [email protected]
Search for more papers by this authorSiro Luvisetto
CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143 Italy
These authors contributed equally to this work.Search for more papers by this authorLuca R. La Rosa
CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143 Italy
Search for more papers by this authorRobert Tamayev
Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, NY, 10461 USA
Search for more papers by this authorAnnabella Pignataro
CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143 Italy
Santa Lucia Foundation, Experimental Neurology Unit, Rome, 00143 Italy
Search for more papers by this authorNadia Canu
CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143 Italy
Department of Systems Medicine, University of Tor Vergata, Rome, 00133 Italy
Search for more papers by this authorLi Yang
Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030 USA
Search for more papers by this authorAlessia P. M. Barbagallo
Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, NY, 10461 USA
Search for more papers by this authorFabrizio Biundo
Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, NY, 10461 USA
Search for more papers by this authorFranco Lombino
Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, NY, 10461 USA
Search for more papers by this authorHui Zheng
Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030 USA
Search for more papers by this authorMartine Ammassari-Teule
CNR - National Research Council, Cell Biology and Neurobiology Institute, Rome, 00143 Italy
Santa Lucia Foundation, Experimental Neurology Unit, Rome, 00143 Italy
Search for more papers by this authorCorresponding Author
Luciano D'Adamio
Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, NY, 10461 USA
Correspondence
Carmela Matrone, Department of Medical Biochemistry, University of Aarhus, 8000 Aarhus C, Denmark. Tel.: +45 87167821; fax: +45 86131160; e-mail: [email protected] or Luciano D'Adamio, Department of Microbiology and Immunology, Einstein College of Medicine, Bronx, New York, NY 10461, USA. Tel.: +1 718 430 3244; fax: +1 718 430 8711; e-mail: [email protected]
Search for more papers by this authorSummary
Processing of Aβ-precursor protein (APP) plays an important role in Alzheimer's disease (AD) pathogenesis. The APP intracellular domain contains residues important in regulating APP function and processing, in particular the 682YENPTY687 motif. To dissect the functions of this sequence in vivo, we created an APP knock-in allele mutating Y682 to Gly (APPYG/YG mice). This mutation alters the processing of APP and TrkA signaling and leads to postnatal lethality and neuromuscular synapse defects when expressed on an APP-like protein 2 KO background. This evidence prompted us to characterize further the APPYG/YG mice. Here, we show that APPYG/YG mice develop aging-dependent decline in cognitive and neuromuscular functions, a progressive reduction in dendritic spines, cholinergic tone, and TrkA levels in brain regions governing cognitive and motor functions. These data are consistent with our previous findings linking NGF and APP signaling and suggest a causal relationship between altered synaptic connectivity, cholinergic tone depression and TrkA signaling deficit, and cognitive and neuromuscular decline in APPYG/YG mice. The profound deficits caused by the Y682 mutation underscore the biological importance of APP and indicate that APPYG/YG are a valuable mouse model to study APP functions in physiological and pathological processes.
References
- Ammassari-Teule M, Sgobio C, Biamonte F, Marrone C, Mercuri NB, Keller F (2009) Reelin haploinsufficiency reduces the density of PV+ neurons in circumscribed regions of the striatum and selectively alters striatal-based behaviors. Psychopharmacology 204, 511–521.
- Arendt T (2009) Synaptic degeneration in Alzheimer′s disease. Acta Neuropathol. 118, 167–179.
- Barbagallo AP, Weldon R, Tamayev R, Zhou D, Giliberto L, Foreman O, D'Adamio L (2010) Tyr682 in the intracellular domain of APP regulates amyloidogenic APP processing in vivo. PLoS ONE 5, e15503.
- Barbagallo AP, Wang Z, Zheng H, D'Adamio L (2011) A single tyrosine residue in the amyloid precursor protein intracellular domain is essential for developmental function. J. Biol. Chem. 286, 8717–8721.
- Bovet D, Bovet-Nitti F, Oliverio A (1969) Genetic aspects of learning and memory in mice. Science 163, 139–149.
- Calissano P, Matrone C, Amadoro G (2010) NGF as a paradigm of neurotrophins related to Alzheimer's disease. Dev. Neurobiol. 70, 372–383.
- D'Amato FR, Zanettini C, Sgobio C, Sarli C, Carone V, Moles A, Ammassari-Teule M (2011) Intensification of maternal care by double-mothering boosts cognitive function and hippocampal morphology in the adult offspring. Hippocampus 21, 298–308.
- Dawson GR, Seabrook GR, Zheng H, Smith DW, Graham S, O'Dowd G, Bowery BJ, Boyce S, Trumbauer ME, Chen HY, Van Der Ploeg LHT, Sirinathsinghji DJS (1999) Age-related cognitive deficits, impaired long-term potentiation and reduction in synaptic marker density in mice lacking the β-amyloid precursor protein. Neuroscience 90, 1–13.
- Fotinopoulou A, Tsachaki M, Vlavaki M, Poulopoulos A, Rostagno A, Frangione B, Ghiso J, Efthimiopoulos S (2005) BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production. J. Biol. Chem. 280, 30768–30772.
- Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356.
- Li H, Wang Z, Wang B, Guo Q, Dolios G, Tabuchi K, Hammer RE, Südhof TC, Wang R, Zheng H (2010) Genetic dissection of the amyloid precursor protein in developmental function and amyloid pathogenesis. J. Biol. Chem. 285, 30598–30605.
- Luvisetto S, Marinelli S, Rossetto O, Montecucco C, Pavone F (2004) Central injection of botulinum neurotoxins: behavioural effects in mice. Behav. Pharmacol. 15, 233–240.
- Luvisetto S, Basso E, Petronilli V, Bernardi P, Forte M (2008) Enhancement of anxiety, facilitation of avoidance behaviour, and occurrence of adult-onset obesity in mice lacking mitochondrial cyclophilin D. Neuroscience 155, 585–596.
- Massett MP, Berk BC (2005) Strain-dependent differences in responses to exercise training in inbred and hybrid mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R1006–R1013.
- Matrone C, Ciotti MT, Marolda R, Mercanti D, Calissano P (2008) NGF and BDNF control amyloidogenic route and Ab production in hippocampal neurons. Proc. Natl. Acad. Sci. USA 105, 13139–13144.
- Matrone C, Marolda R, Ciotti MT, Ciafrè S, Mercanti D, Calissano P (2009) Tyrosine Kinase NGF receptor switches from pro-survival to pro-apoptotic activity via Abeta mediated phosphorylation. Proc. Natl. Acad. Sci. USA 106, 11358–11360.
- Matrone C, Barbagallo AP, La Rosa LR, Florenzano F, Ciotti MT, Mercanti D, Chao MV, Calissano P, D'Adamio L (2011) APP is phosphorylated by TrkA and regulates NGF/TrkA signaling. J. Neurosci. 31, 11756–11761.
- Matsuda S, Matsuda Y, D'Adamio L (2003) Amyloid beta protein precursor (AbetaPP), but not AbetaPP-like protein 2, is bridged to the kinesin light chain by the scaffold protein JNK-interacting protein 1. J. Biol. Chem. 278, 38601–38606.
- Matsuda S, Giliberto L, Matsuda Y, Davies P, McGowan E, Pickford F, Ghiso J, Frangione B, D'Adamio L (2005) The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production. J. Biol. Chem. 280, 28912–28916.
- Matsuda S, Giliberto L, Matsuda Y, McGowan EM, D'Adamio L (2008) BRI2 inhibits amyloid beta-peptide precursor protein processing by interfering with the docking of secretases to the substrate. J. Neurosci. 28, 8668–8676.
- Matsuda S, Matsuda Y, Snapp EL, D'Adamio L (2011) Maturation of BRI2 generates a specific inhibitor that reduces APP processing at the plasma membrane and in endocytic vesicles. Neurobiol. Aging 32, 1400–1408.
- Niewiadomska G, Mietelska-Porowska A, Mazurkiewicz M (2011) The cholinergic system, nerve growth factor and the cytoskeleton. Behav. Brain Res. 221, 515–526.
- Roncarati R, Sestan N, Scheinfeld MH, Berechid BE, Lopez PA, Meucci O, McGlade JC, Rakic P, D'Adamio L (2002) The gamma-secretase-generated intracellular domain of beta-amyloid precursor protein binds numb and inhibits notch signaling. Proc. Natl. Acad. Sci. USA 99, 7102–7107.
- Ruberti F, Capsoni S, Comparini A, Di Daniel E, Franzot J, Gonfloni S, Rossi G, Berardi N, Cattaneo A (2000) Phenotypic knockout of nerve growth factor in adult transgenic mice reveals severe deficits in basal forebrain cholinergic neurons, cell death in the spleen, and skeletal muscle dystrophy. J. Neurosci. 20, 2589–2601.
- Russo C, Dolcini V, Salis S, Venezia V, Zambrano N, Russo T, Schettini G (2002) Signal transduction through tyrosine-phosphorylated C-terminal fragments of amyloid precursor protein via an enhanced interaction with Shc/Grb2 adaptor proteins in reactive astrocytes of Alzheimer's disease brain. J. Biol. Chem. 277, 35282–35288.
- Scheinfeld MH, Matsuda S, D'Adamio L (2003a) JNK-interacting protein-1 promotes transcription of A beta protein precursor but not A beta precursor-like proteins, mechanistically different than Fe65. Proc. Natl. Acad. Sci. USA 100, 1729–1734.
- Scheinfeld MH, Ghersi E, Davies P, D'Adamio L (2003b) Amyloid beta protein precursor is phosphorylated by JNK-1 independent of, yet facilitated by, JNK-interacting protein (JIP)-1. J. Biol. Chem. 278, 42058–42063.
- Schliebs R, Arendt T (2011) The cholinergic system in aging and neuronal degeneration. Behav. Brain Res. 221, 555–563.
- Taglialatela G, Hogan D, Zhang WR, Dineley KT (2009) Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition. Behav. Brain Res. 200, 95–99.
- Tamayev R, Zhou D, D'Adamio L (2009) The interactome of the amyloid beta precursor protein family members is shaped by phosphorylation of their intracellular domains. Mol. Neurodegener. 4, 28.
- Tamayev R, Matsuda S, Giliberto L, Arancio O, D'Adamio L (2011) APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant. EMBO J. 30, 2501–2509.
- Tamayev R, Matsuda S, Arancio O, D'Adamio L (2012) beta- but not gamma-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia. EMBO Mol. Med. 4, 171–179.
- Tarr PE, Roncarati R, Pelicci G, Pelicci PG, D'Adamio L (2002) Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic tail promotes interaction with Shc. J. Biol. Chem. 277, 16798–16804.
- Vidal R, Frangione B, Rostagno A, Mead S, Revesz T, Plant G, Ghiso J (1999) A stop-codon mutation in the BRI gene associated with familial British dementia. Nature 399, 776–781.
- Yang L, Wang B, Long C, Wu G, Zheng H (2007) Increased asynchronous release and aberrant calcium channel activation in amyloid precursor protein deficient neuromuscular synapses. Neuroscience 149, 768–778.
- Zhou D, Noviello C, D'Ambrosio C, Scaloni A, D'Adamio L (2004) Growth factor receptor-bound protein 2 interaction with the tyrosine-phosphorylated tail of amyloid beta precursor protein is mediated by its Src homology 2 domain. J. Biol. Chem. 279, 25374–25380.
- Zhou D, Zambrano N, Russo T, D'Adamio L (2009) Phosphorylation of a tyrosine in the amyloid-beta protein precursor intracellular domain inhibits Fe65 binding and signaling. J. Alzheimers Dis. 16, 301–307.
