Enhanced amyloidogenic processing of the beta-amyloid precursorprotein in gene-targeted mice bearing the Swedish familialAlzheimer's disease mutations and a ''humanized'' A beta sequence
A.G. Reaume
Bok Engelsk 1996
| Utgitt | 1996
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| Omfang | Side 23380- 23388
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| Opplysninger | The processing of the beta-amyloid precursor protein (APP) in vivohas been characterized in a novel animal model that recapitulates, inpart, the APP genotype of a familial form of Alzheimer's disease(AD). A gene-targeting strategy was used to introduce the Swedishfamilial AD mutations and convert mouse A beta to the human sequence.The mutant APP is expressed at normal levels in brain, and cleavageat the mutant beta-secretase site is both accurate and enhanced.Furthermore, human A beta production is significantly increased tolevels 9-fold greater than those in normal human brain whilenonamyloidogenic processing is depressed. The results on A betaproduction extend similar findings obtained in cell culture to thebrain of an animal and substantiate A beta as a etiological factor inSwedish familial AD. These animals provide several distinguishingfeatures over others created by conventional transgenicmethodologies. The spatial and temporal expression patterns of humanA beta are expected to be faithfully reproduced because the geneencoding the mutant APP remains in its normal chromosomal context.Thus, the neuropathological consequences of human A betaoverproduction can be evaluated longitudinally in the absence ofpotential mitigating effects of APP overexpression or presence of themouse A beta peptide.
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