Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology
Christine Sturchler-Pierrat,Dorothee Abramowski,Mairead Duke,Karl-Heinz Wiederhold,Claudia Mistl,Sabin Rothacher,Birgit Ledermann,Kurt Bürki,Peter Frey,Paolo Paganetti,Caroline Waridel,Michael E. Calhoun,Mathias Jucker,Alphonse Probst,Matthias Staufenbiel,Bernd Sommer +15 more
TLDR
These mice resemble major features of AD pathology and suggest a central role of A beta in the pathogenesis of the disease.Abstract:
Mutations in the amyloid precursor protein (APP) gene cause early-onset familial Alzheimer disease (AD) by affecting the formation of the amyloid β (Aβ) peptide, the major constituent of AD plaques. We expressed human APP751 containing these mutations in the brains of transgenic mice. Two transgenic mouse lines develop pathological features reminiscent of AD. The degree of pathology depends on expression levels and specific mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670/671 combined with the V717I mutation causes Aβ deposition in neocortex and hippocampus of 18-month-old transgenic mice. The deposits are mostly of the diffuse type; however, some congophilic plaques can be detected. In mice with 7-fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appear at 6 months, which increase with age and are Congo Red-positive at first detection. These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inflammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology. The immunoreactivity is exclusively found in congophilic senile plaques of both lines. In the higher expressing line, elevated tau phosphorylation can be demonstrated biochemically in 6-month-old animals and increases with age. These mice resemble major features of AD pathology and suggest a central role of Aβ in the pathogenesis of the disease.read more
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Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation.
Holly Oakley,Sarah L. Cole,Sreemathi Logan,Erika Maus,Pei Shao,Jeffery Craft,Angela L. Guillozet-Bongaarts,Masuo Ohno,John F. Disterhoft,Linda J. Van Eldik,Robert W. Berry,Robert Vassar +11 more
TL;DR: 5XFAD mice rapidly recapitulate major features of AD amyloid pathology and may be useful models of intraneuronal Aβ42-induced neurodegeneration and amyloids plaque formation.
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High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.
Lennart Mucke,Eliezer Masliah,Gui-Qiu Yu,Margaret Mallory,Edward Rockenstein,Gwen Tatsuno,Kang Hu,Dora Kholodenko,Kelly Johnson-Wood,Lisa McConlogue +9 more
TL;DR: It is concluded that Aβ is synaptotoxic even in the absence of plaques and that high levels of Aβ1–42 are insufficient to induce plaque formation in mice expressing wild-type hAPP, supporting the emerging view that plaque-independent Aβ toxicity plays an important role in the development of synaptic deficits in AD and related conditions.
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Translating cell biology into therapeutic advances in Alzheimer's disease
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Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models
Lars M. Ittner,Yazi D. Ke,Fabien Delerue,Mian Bi,Amadeus Gladbach,Janet van Eersel,Heidrun Wölfing,Billy Chieng,MacDonald J. Christie,Ian A. Napier,Anne Eckert,Matthias Staufenbiel,Edna C. Hardeman,Jürgen Götz +13 more
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Diffusion in brain extracellular space.
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TL;DR: Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer β-amyloid (Aβ) precursor protein containing a Lys670 → Asn, Met671 → Leu mutation had normal learning and memory but showed impairment by 9 to 10 months of age.
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TL;DR: Transgenic mice that express high levels of human mutant APP support a primary role for APP/Aβ in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.
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