An Intracellular Threonine of Amyloid-β Precursor Protein Mediates Synaptic Plasticity Deficits and Memory Loss

Mutations in Amyloid-ß Precursor Protein (APP) and BRI2/ITM2b genes cause Familial Alzheimer and Danish Dementias (FAD/FDD), respectively. APP processing by BACE1, which is inhibited by BRI2, yields sAPPß and ß-CTF. ß-CTF is cleaved by gamma-secretase to produce Aß. A knock-in mouse model of FDD, called FDDKI, shows deficits in memory and synaptic plasticity, which can be attributed to sAPPß/ß-CTF but not Aß. We have investigated further the pathogenic function of ß-CTF focusing on Thr668 of ß-CTF because phosphorylation of Thr668 is increased in AD cases. We created a knock-in mouse bearing a Thr668Ala mutation (APPTA mice) that prevents phosphorylation at this site. This mutation prevents the development of memory and synaptic plasticity deficits in FDDKI mice. These data are consistent with a role for the carboxyl-terminal APP domain in the pathogenesis of dementia and suggest that averting the noxious role of Thr668 is a viable therapeutic strategy for human dementias.

[1]  E. Snapp,et al.  Maturation of BRI2 generates a specific inhibitor that reduces APP processing at the plasma membrane and in endocytic vesicles , 2011, Neurobiology of Aging.

[2]  Kristopher L. Nazor,et al.  Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells , 2012, Nature.

[3]  P. Pelicci,et al.  Tyrosine Phosphorylation of the β-Amyloid Precursor Protein Cytoplasmic Tail Promotes Interaction with Shc* , 2002, The Journal of Biological Chemistry.

[4]  P. Davies,et al.  Amyloid (cid:1) Protein Precursor Is Phosphorylated by JNK-1 Independent of, yet Facilitated by, JNK-Interacting Protein (JIP)-1* , 2022 .

[5]  A. Scaloni,et al.  Growth Factor Receptor-bound Protein 2 Interaction with the Tyrosine-phosphorylated Tail of Amyloid β Precursor Protein Is Mediated by Its Src Homology 2 Domain* , 2004, Journal of Biological Chemistry.

[6]  E. McGowan,et al.  BRI2 Inhibits Amyloid β-Peptide Precursor Protein Processing by Interfering with the Docking of Secretases to the Substrate , 2008, The Journal of Neuroscience.

[7]  Rick A Bevins,et al.  Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study 'recognition memory' , 2006, Nature Protocols.

[8]  L. Nicholson,et al.  The prolyl isomerase Pin1 regulates amyloid precursor protein processing and amyloid-β production , 2006, Nature.

[9]  P. Davies,et al.  The Familial Dementia BRI2 Gene Binds the Alzheimer Gene Amyloid-β Precursor Protein and Inhibits Amyloid-β Production* , 2005, Journal of Biological Chemistry.

[10]  R. Roncarati,et al.  Jun NH2-terminal Kinase (JNK) Interacting Protein 1 (JIP1) Binds the Cytoplasmic Domain of the Alzheimer's β-Amyloid Precursor Protein (APP)* , 2002, The Journal of Biological Chemistry.

[11]  L. D’Adamio,et al.  Inhibition of γ-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia , 2012, Molecular Neurodegeneration.

[12]  Y. Kirino,et al.  Phosphorylation-dependent Regulation of the Interaction of Amyloid Precursor Protein with Fe65 Affects the Production of β-Amyloid* , 2001, The Journal of Biological Chemistry.

[13]  M. Scheinfeld,et al.  JNK-interacting protein-1 promotes transcription of Aβ protein precursor but not Aβ precursor-like proteins, mechanistically different than Fe65 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[14]  R. Shin,et al.  Amyloid precursor protein cytoplasmic domain with phospho-Thr668 accumulates in Alzheimer’s disease and its transgenic models: a role to mediate interaction of Aβ and tau , 2007, Acta Neuropathologica.

[15]  R. Shin,et al.  Amyloid precursor protein cytoplasmic domain with phospho-Thr668 accumulates in Alzheimer's disease and its transgenic models: a role to mediate interaction of Abeta and tau. , 2007, Acta neuropathologica.

[16]  R. Vidal,et al.  Generation and Initial Characterization of FDD Knock In Mice , 2009, PloS one.

[17]  Hui Zheng,et al.  The Intracellular Threonine of Amyloid Precursor Protein That Is Essential for Docking of Pin1 Is Dispensable for Developmental Function , 2011, PloS one.

[18]  S. Arena,et al.  Hyperphosphorylation of JNK-interacting Protein 1, a Protein Associated with Alzheimer Disease*S , 2006, Molecular & Cellular Proteomics.

[19]  L. D’Adamio,et al.  Increased AβPP processing in familial Danish dementia patients. , 2011, Journal of Alzheimer's disease : JAD.

[20]  Dawang Zhou,et al.  Tyr682 in the Intracellular Domain of APP Regulates Amyloidogenic APP Processing In Vivo , 2010, PloS one.

[21]  Dawang Zhou,et al.  The interactome of the amyloid β precursor protein family members is shaped by phosphorylation of their intracellular domains , 2009, Molecular Neurodegeneration.

[22]  O. Arancio,et al.  APP heterozygosity averts memory deficit in knockin mice expressing the Danish dementia BRI2 mutant , 2011, The EMBO journal.

[23]  K. Lu,et al.  Pin1 in Alzheimer's disease: multiple substrates, one regulatory mechanism? , 2007, Biochimica et biophysica acta.

[24]  O. Arancio,et al.  Danish dementia mice suggest that loss of function and not the amyloid cascade causes synaptic plasticity and memory deficits , 2010, Proceedings of the National Academy of Sciences.

[25]  O. Arancio,et al.  β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia , 2012, Molecular Neurodegeneration.

[26]  L. D’Adamio,et al.  Amyloid β Protein Precursor (AβPP), but Not AβPP-like Protein 2, Is Bridged to the Kinesin Light Chain by the Scaffold Protein JNK-interacting Protein 1* , 2003, Journal of Biological Chemistry.

[27]  T Bek,et al.  A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Toshiharu Suzuki,et al.  Membrane-Microdomain Localization of Amyloid β-Precursor Protein (APP) C-terminal Fragments Is Regulated by Phosphorylation of the Cytoplasmic Thr668 Residue* , 2012, The Journal of Biological Chemistry.

[29]  B. Ghetti,et al.  Modeling familial British and Danish dementia , 2010, Brain Structure and Function.

[30]  J. Ghiso,et al.  BRI2 interacts with amyloid precursor protein (APP) and regulates amyloid beta (Abeta) production. , 2005, The Journal of biological chemistry.

[31]  Dawang Zhou,et al.  Phosphorylation of a tyrosine in the amyloid-beta protein precursor intracellular domain inhibits Fe65 binding and signaling. , 2009, Journal of Alzheimer's disease : JAD.

[32]  O. Arancio,et al.  Caspase-9 mediates synaptic plasticity and memory deficits of Danish dementia knock-in mice: caspase-9 inhibition provides therapeutic protection , 2012, Molecular Neurodegeneration.

[33]  R. Tanzi,et al.  The Genetics of Alzheimer Disease: Back to the Future , 2010, Neuron.

[34]  A. Scaloni,et al.  Proteomic Characterization of a Mouse Model of Familial Danish Dementia , 2012, Journal of biomedicine & biotechnology.

[35]  P. Rakic,et al.  The gamma-secretase-generated intracellular domain of beta-amyloid precursor protein binds Numb and inhibits Notch signaling. , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[36]  T. Russo,et al.  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* , 2002, The Journal of Biological Chemistry.

[37]  Agueda Rostagno,et al.  A stop-codon mutation in the BRI gene associated with familial British dementia , 1999, Nature.

[38]  A. Jiménez-Escrig,et al.  Molecular biology and genetics of Alzheimer's disease , 1995, European journal of neurology.

[39]  P. Davies,et al.  The familial dementia BRI2 gene binds the Alzheimer gene amyloid-beta precursor protein and inhibits amyloid-beta production. , 2005, The Journal of biological chemistry.

[40]  Y. Sano,et al.  Physiological Mouse Brain Aβ Levels Are Not Related to the Phosphorylation State of Threonine-668 of Alzheimer's APP , 2006, PloS one.

[41]  G M Rose,et al.  Exposing rats to a predator impairs spatial working memory in the radial arm water maze , 1999, Hippocampus.

[42]  L. D’Adamio,et al.  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. , 2003, The Journal of biological chemistry.

[43]  Hui Zheng,et al.  Tyr682 in the Aβ‐precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance , 2012, Aging cell.

[44]  M. Scheinfeld,et al.  JNK-interacting protein-1 promotes transcription of A beta protein precursor but not A beta precursor-like proteins, mechanistically different than Fe65. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[45]  J. Ghiso,et al.  BRI2 Interacts with Amyloid Precursor Protein (APP) and Regulates Amyloid β (Aβ) Production* , 2005, Journal of Biological Chemistry.

[46]  P. Rakic,et al.  The γ-secretase-generated intracellular domain of β-amyloid precursor protein binds Numb and inhibits Notch signaling , 2002, Proceedings of the National Academy of Sciences of the United States of America.