Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein

• Published in: Nature (London) Vol. 373; no. 6514; pp. 523 - 527
• Main Authors: Games, Dora, Adams, David, Alessandrini, Ree, Barbour, Robin, Borthelette, Patricia, Blackwell, Catherine, Carr, Tony, Clemens, James, Donaldson, Thomas, Gillespie, Frances, Guido, Terry, Hagopian, Stephanie, Johnson-Wood, Kelly, Khan, Karen, Lee, Mike, Leibowitz, Paul, Lieberburg, Ivan, Little, Sheila, Masliah, Eliezer, McConlogue, Lisa, Montoya-Zavala, Martin, Mucke, Lennart, Paganini, Lisa, Penniman, Elizabeth, Power, Mike, Schenk, Dale, Seubert, Peter, Snyder, Ben, Soriano, Ferdie, Tan, Hua, Vitale, James, Wadsworth, Sam, Wolozin, Ben, Zhao, Jun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 09.02.1995
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - genetics; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; amyloid precursor protein; animal models; Animals; Base Sequence; beta -amyloid; Biological and medical sciences; Brain - metabolism; Brain - pathology; corpus callosum; cortex; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Primers; hippocampus; Humans; Immunoenzyme Techniques; Medical sciences; Mice; Mice, Transgenic; Microscopy, Confocal; Molecular Sequence Data; Mutation; neurofibrillary tangles; Neurology; Platelet-Derived Growth Factor - genetics; Platelet-Derived Growth Factor - metabolism; point mutation; senile plaques; transgenic mice; Nervous system diseases; Alzheimer disease; Central nervous system disease; Transgenic animal; Degenerative disease; Amyloid precursor protein; Cerebral disorder
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/373523a0

Alzheimer's disease (AD) is the most common cause of progressive intellectual failure in aged humans. AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary tangle formation and gliosis. The amyloid plaques are composed of amyloid beta-peptide (A beta), a 40-42-amino-acid fragment of the beta-amyloid precursor protein (APP). A primary pathogenic role for APP/A beta is suggested by missense mutations in APP that are tightly linked to autosomal dominant forms of AD. A major obstacle to elucidating and treating AD has been the lack of an animal model. Animals transgenic for APP have previously failed to show extensive AD-type neuropathology, but we now report the production of transgenic mice that express high levels of human mutant APP (with valine at residue 717 substituted by phenylalanine) and which progressively develop many of the pathological hallmarks of AD, including numerous extracellular thioflavin S-positive A beta deposits, neuritic plaques, synaptic loss, astrocytosis and microgliosis. These mice support a primary role for APP/A beta in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.