title: JNK-interacting protein 1 mediates Alzheimer's-like pathological features in AICD-transgenic mice.
abstract: Amyloid precursor protein, which generates amyloid beta peptides, is intimately associated with Alzheimer's disease (AD) pathogenesis. We previously showed that transgenic mice overexpressing amyloid precursor protein intracellular domain (AICD), a peptide generated simultaneously with amyloid beta, develop AD-like pathologies, including hyperphosphorylated tau, loss of synapses, and memory impairments. AICD is known to bind c-Jun N-terminal kinase (JNK)-interacting protein 1 (JIP1), a scaffold protein that associates with and activates JNK. The aim of this study was to examine the role of JIP1 in AICD-induced AD-like pathologies in vivo, since the JNK pathway is aberrantly activated in AD brains and contributes to AD pathologies. We generated AICD-Tg mice lacking the JIP1 gene (AICD; JIP1(-/-)) and found that although AICD; JIP1(-/-) mice exhibit increased AICD, the absence of JIP1 results in decreased levels of hyperphosphorylated tau and activated JNK. AICD; JIP1(-/-) mice are also protected from synaptic loss and show improved performance in behavioral tests. These results suggest that JIP1 mediates AD-like pathologies in AICD-Tg mice and that JNK signaling may contribute to amyloid-independent mechanisms of AD pathogenesis.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA. Electronic address: margevd@ccf.org.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Margevicius
authors.affiliation: Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Chinthasagar
authors.initials: C
authors.lastname: Bastian
authors.affiliation: Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School and Howard Hughes Medical Institute, Worcestor, MA, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Department of Neurosciences, Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Sanjay W
authors.initials: SW
authors.lastname: Pimplikar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C490665:Mapk8ip protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases
keywords: AICD; APP; Alzheimer's; JNK; JNK-interacting protein 1; Tau