Amyloid plaques, neurofibrillary tangles and neuronal loss in brains of transgenic mice overexpressing a C-terminal fragment of human amyloid precursor protein.
Alzheimer's disease (AD) affects more than 30% of people over 80 years of age. 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), referred to as beta/A4, and contains the amino-acid residues 29-42 that are normally embedded in the membrane-spanning region of the precursor. The cellular source of APP and the relationship of its deposition to the neuropathology of AD is unknown. To investigate the relationship between APP overexpression and amyloidogenesis, we have developed a vector to drive expression specifically in neurons of a C-terminal fragment of APP that contains the beta/A4 region, and have used a transgenic mouse system 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.
Kawabata
S
S
Department of Geriatrics and Adult Development, Mt Sinai Medical Center, New York, New York 10029.
Higgins
G A
GA
Gordon
J W
JW
D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000686:Amyloidosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry; D004195:Disease Models, Animal; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016874:Neurofibrillary Tangles / Q000473:pathology*; D009474:Neurons / Q000737:chemistry / Q000473:pathology*; D010446:Peptide Fragments / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments