Generation of a humanized Aß expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology
Por:
Baglietto-Vargas D., Forner S., Cai L., Martini A.C., Trujillo-Estrada L., Swarup V., Nguyen M.M.T., Do Huynh K., Javonillo D.I., Tran K.M., Phan J., Jiang S., Kramár E.A., Nuñez-Diaz C., Balderrama-Gutierrez G., Garcia F., Childs J., Rodriguez-Ortiz C.J., Garcia-Leon J.A., Kitazawa M., Shahnawaz M., Matheos D.P., Ma X., Da Cunha C., Walls K.C., Ager R.R., Soto C., Gutierrez A., Moreno-Gonzalez I., Mortazavi A., Tenner A.J., MacGregor G.R., Wood M., Green K.N., LaFerla F.M.
Publicada:
1 ene 2021
Resumen:
The majority of Alzheimer’s disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aß under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aß sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aß sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAß expression, rescues cognition and reduces the formation of PAS granules. © 2021, The Author(s).
Filiaciones:
Baglietto-Vargas D.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Department of Neurobiology and Behavior, University of California, Irvine, CA, United States
Department of Cell Biology, Genetic and Physiology, Faculty of Sciences, Instituto de Investigacion Biomedica de Malaga-IBIMA, Networking Research Center on Neurodegenerative Diseases (CIBERNED), University of Malaga, Malaga, Spain
Forner S.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Cai L.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Martini A.C.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Trujillo-Estrada L.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Department of Cell Biology, Genetic and Physiology, Faculty of Sciences, Instituto de Investigacion Biomedica de Malaga-IBIMA, Networking Research Center on Neurodegenerative Diseases (CIBERNED), University of Malaga, Malaga, Spain
Swarup V.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Department of Neurobiology and Behavior, University of California, Irvine, CA, United States
Nguyen M.M.T.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Do Huynh K.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Javonillo D.I.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Tran K.M.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Phan J.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Jiang S.:
Department of Developmental and Cell Biology, University of California, Irvine, CA, United States
Kramár E.A.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Department of Neurobiology and Behavior, University of California, Irvine, CA, United States
Nuñez-Diaz C.:
Department of Cell Biology, Genetic and Physiology, Faculty of Sciences, Instituto de Investigacion Biomedica de Malaga-IBIMA, Networking Research Center on Neurodegenerative Diseases (CIBERNED), University of Malaga, Malaga, Spain
Balderrama-Gutierrez G.:
Department of Developmental and Cell Biology, University of California, Irvine, CA, United States
Garcia F.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Department of Neurobiology and Behavior, University of California, Irvine, CA, United States
Childs J.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Department of Neurobiology and Behavior, University of California, Irvine, CA, United States
Rodriguez-Ortiz C.J.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Division of Occupational and Environmental Medicine, Department of Medicine. Center for Occupational and Environmental Health (COEH), University of California, Irvine, CA, United States
Garcia-Leon J.A.:
Department of Cell Biology, Genetic and Physiology, Faculty of Sciences, Instituto de Investigacion Biomedica de Malaga-IBIMA, Networking Research Center on Neurodegenerative Diseases (CIBERNED), University of Malaga, Malaga, Spain
Kitazawa M.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Division of Occupational and Environmental Medicine, Department of Medicine. Center for Occupational and Environmental Health (COEH), University of California, Irvine, CA, United States
Shahnawaz M.:
The Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
Matheos D.P.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Department of Neurobiology and Behavior, University of California, Irvine, CA, United States
Ma X.:
Department of Developmental and Cell Biology, University of California, Irvine, CA, United States
Da Cunha C.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Walls K.C.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Ager R.R.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Soto C.:
The Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
Gutierrez A.:
Department of Cell Biology, Genetic and Physiology, Faculty of Sciences, Instituto de Investigacion Biomedica de Malaga-IBIMA, Networking Research Center on Neurodegenerative Diseases (CIBERNED), University of Malaga, Malaga, Spain
Moreno-Gonzalez I.:
Department of Cell Biology, Genetic and Physiology, Faculty of Sciences, Instituto de Investigacion Biomedica de Malaga-IBIMA, Networking Research Center on Neurodegenerative Diseases (CIBERNED), University of Malaga, Malaga, Spain
The Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
Mortazavi A.:
Department of Developmental and Cell Biology, University of California, Irvine, CA, United States
Tenner A.J.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Department of Neurobiology and Behavior, University of California, Irvine, CA, United States
Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, United States
MacGregor G.R.:
Department of Developmental and Cell Biology, University of California, Irvine, CA, United States
Wood M.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Department of Neurobiology and Behavior, University of California, Irvine, CA, United States
Green K.N.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Department of Neurobiology and Behavior, University of California, Irvine, CA, United States
LaFerla F.M.:
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, United States
Department of Neurobiology and Behavior, University of California, Irvine, CA, United States
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