Genetically altered transgenic models of Alzheimer's disease.
Abnormal processing and aggregation of synaptic proteins might play an important role in the pathogenesis of neurodegenerative disorders. Among them, amyloid precursor protein (APP) has been clearly associated with Alzheimer's disease (AD) and various transgenic (tg) animal models have been developed where mutant APP is overexpressed under the regulatory control of neuronal promoters. These studies have shown that AD-like pathology (namely plaques and synapse damage) begins to develop at 6-8 months of age in mice expressing human APP under Thy1, platelet-derived growth factor (B-chain) or protease-resistant prion protein promoters, provided that levels of APP are higher than 5-7 fold of endogenous levels. None of these models have shown the presence of tangles; however, tau-immunoreactive neurites in plaques and astroglial/microglial activation are observed after 12 months of age. Neuronal loss and alterations of synaptic function and connectivity are found in the CA1 region in the PDAPP tg mice lacking the Swiss Webster background. Co-expression of other genes associated with AD modify this phenotype, for example, mutant presenilin 1 accelerates the onset of plaque formation, transforming growth factor beta enhances vascular amyloidosis, and apolipoprotein E decreases amyloid deposition. In conclusion, tg mice which are capable of mimicking some aspects of AD (provided that high enough levels of expression are achieved) can potentially be used to test novel drugs for the treatment of neurodegenerative disorders.
Masliah
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Department of Neurosciences and Pathology, University of California, San Diego School of Medicine, La Jolla 92093-0624, USA.
Rockenstein
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D000544:Alzheimer Disease / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics*; D004195:Disease Models, Animal; D006824:Hybridization, Genetic; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics
D016564:Amyloid beta-Protein Precursor