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

Dora Games, David Adams, Ree Alessandrini, Robin Barbour, Patricia Borthelette, Catherine Blackwell, Tony Carr, James Clemens, Thomas Donaldson, Frances Gillespie, Terry Guido, Stephanie Hagopian, Kelly Johnson-Wood, Karen Khan, Mike Lee, Paul Leibowitz, Ivan Lieberburg, Sheila Little, Eliezer Masliah, Lisa McConlogueMartin Montoya-Zavala, Lennart Mucke, Lisa Paganini, Elizabeth Penniman, Mike Power, Dale Schenk, Peter Seubert, Ben Snyder, Ferdie Soriano, Hua Tan, James Vitale, Sam Wadsworth, Ben Wolozin, Jun Zhao

Research output: Contribution to journalArticlepeer-review

2113 Scopus citations

Abstract

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 β-peptide (Aβ), a 40–42-amino-acid fragment of the β-amyloid precursor protein (APP)1. A primary pathogenic role for APP/Aβ is sug-gested by missense mutations in APP that are tightly linked to autosomal dominant forms of AD2, 3. 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 neuropathology4-10, 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 Aβ deposits, neuritic plaques, synaptic loss, astrocytosis and microgliosis. These mice support a primary role for APP/Aβ in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.

Original languageEnglish (US)
Pages (from-to)523-527
Number of pages5
JournalNature
Volume373
Issue number6514
DOIs
StatePublished - Feb 9 1995

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