Progressive neuropathology and cognitive decline in a single Arctic APP transgenic mouse model

• Published in: Neurobiology of aging Vol. 32; no. 2; pp. 280 - 292
• Main Authors: Rönnbäck, Annica, Zhu, Shunwei, Dillner, Karin, Aoki, Mikio, Lilius, Lena, Näslund, Jan, Winblad, Bengt, Graff, Caroline
• Format: Journal Article
• Language: English
• Published: London Elsevier Inc 01.02.2011; Elsevier
• Subjects: Age Factors; Alanine - genetics; Alzheimer disease; Alzheimer Disease - complications; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Amyloid beta; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Animals; Arctic mutation; Barnes maze; Behavior; Biological and medical sciences; Brain - metabolism; Brain - pathology; Cognition Disorders - etiology; Cognition Disorders - genetics; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Development. Senescence. Regeneration. Transplantation; Disease Progression; Enzyme-Linked Immunosorbent Assay - methods; Escape Reaction - physiology; Exploratory Behavior - physiology; Fundamental and applied biological sciences. Psychology; Glycine - genetics; Humans; Internal Medicine; Learning and memory; Learning Disorders - etiology; Maze Learning - physiology; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Transgenic; Mutation - genetics; Neurology; Peptide Fragments - metabolism; Statistics, Nonparametric; Transgenic animal model; Vertebrates: nervous system and sense organs; Learning and memory; Amyloid beta; Arctic mutation; Alzheimer disease; Behavior; Barnes maze; Transgenic animal model; Animal model; Nervous system diseases; Senescence; Memory; Rodentia; Transgenic animal; Cognition; Cerebral disorder; Learning; Vertebrata; Mammalia; Acquisition process; Mouse; β Amyloid protein; Central nervous system disease; Degenerative disease; Mutation
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2009.02.021

Abstract The Arctic APP mutation (E693G) leads to dementia with clinical features similar to Alzheimer disease (AD), but little is known about the pathogenic mechanism of this mutation. To address this question, we have generated a transgenic mouse model, TgAPParc, with neuron-specific expression of human APP with the Arctic mutation (hAPParc). Heterozygous mice from two separate founder lines with different levels of expression of hAPParc were analyzed with respect to brain morphology and behavior every 3 months until the age of 18 months. Standard histological stainings and immunohistochemistry using a panel of Aβ antibodies showed an age- and dose-dependant progression of amyloid deposition in the brain, starting in the subiculum and spreading to the thalamus. Cognitive behavioral testing revealed deficits in hippocampus-dependent spatial learning and memory in the Barnes maze test. This study demonstrates that the Arctic APP mutation is sufficient to cause amyloid deposition and cognitive dysfunction, and thus the TgAPParc mouse model provides a valuable tool to study the effect of the Arctic mutation in vivo without possible confounding effect of other APP mutations.