Nature 354, 476 - 478 (12 December 1991); doi:10.1038/354476a0

Amyloid plaques, neurofibrillary tangles and neuronal loss in brains of transgenic mice overexpressing a C-terminal fragment of human amyloid precursor protein

Shigeki Kawabata^*†, Gerald A. Higgins^‡ & Jon W. Gordon^*§

^* Department of Geriatrics and Adult Development, and ^§ Department of Obs/Gyn Reproductive Science, Mt Sinai Medical Center, 2056 Annenberg, New York, New York 10029, USA
^† Yamanouchi Pharmaceutical Co. Ltd, Tokyo 103, Japan
^‡ Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
To whom correspondence should be addressed

ALZHEIMER'S disease (AD) affects more than 30% of people over 80 years of age^1,2. The aetiology and pathogenesis of this progressive dementia is poorly understood, but symptomatic disease is associated histopathologically with amyloid plaques, neurofibrillary tangles and neuronal loss primarily in the temporal lobe and neocortex of the brain. The core of the extracellular plaque is a derivative of the amyloid precursor protein (APP)³, referred to as /A4 (refs ^4–6), and contains the amino-acid residues 29–42 that are normally embedded in the membrane-spanning region of the precursor³. The cellular source of APP and the relationship of its deposition to the neuropathology of AD is unknown. To investigate the relationship between APP over-expression and amyloidogenesis, we have developed a vector to drive expression specifically in neurons of a C-terminal fragment of APP that contains the /A4 region, and have used a transgenic mouse system^7,8 to insert and express this construct. We report here that overexpression of this APP transgene in neurons is sufficient to produce extracellular dense-core amyloid plaques, neurofibrillary tangles and neuronal degeneration similar to that in the AD brain.

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