Pii: S0531-5565(00)00149-2

In transgenic mice that overexpress mutant Amyloid Precursor Protein [V717I], or APP/London (APP/Lo) (1999a. Early phenotypic changes in transgenic mice that overexpress different mutants of Amyloid Precursor Protein in brain. J. Biol. Chem. 274, 6483±6492; 1999b. Premature death in transgenic mice that overexpress mutant Amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. Neuroscience 91, 819±830) the AD related phenotype of plaque and vascular amyloid pathology is late (12±15 months). This typical and diagnostic pathology is thereby dissociated in time from early symptoms (3±9 months) that include disturbed behavior, neophobia, aggression, glutamate excitotoxicity, defective cognition and decreased LTP. The APP/Lo transgenic mice are therefore a very interesting model to study early as well as late pathology, including the effect of age. In ageing APP*Lo mice, brain soluble and especially ainsolubleo amyloid peptides dramatically increased, while normalized levels of secreted APPsa and APPsb, as well as cell-bound b-C-stubs, remained remarkably constant, indicating normal aand b-secretase processing of APP. In double transgenic mice, i.e. APP=Lo £ PS1; clinical mutant PS1[A246E] but not wild-type human PS1 increased Ab, and plaques and vascular amyloid developed at age 6±9 months. The PS1 mutant caused increasing Ab42 production, while ageing did not. Amyloid deposits are thus formed, not by overproduction of Ab, but by lack of clearance and/or degradation in the brain of ageing APP/Lo transgenic mice. The clearance pathways of the cerebral amyloid peptides are therefore valuable targets for fundamental research and for therapeutic potential. Although hyper-phosphorylated protein tau was evident in swollen neurites around the amyloid plaques, neuro®brillary pathology is not observed and the atangleo aspect of AD pathology is therefore still missing from all current transgenic aamyloido models. Also the aApoE4o risk for late onset AD remains a problem for I. Dewachter et al. / Experimental Gerontology 35 (2000) 831±841 831 Experimental Gerontology 35 (2000) 831±841 www.elsevier.nl/locate/expgero 0531-5565/00/$ see front matter q 2000 Elsevier Science Inc. All rights reserved. PII: S0531-5565(00)00149-2 * Corresponding author. Tel.: 132-16-345888; fax: 132-16-345871. E-mail address: [email protected] (F. Van Leuven). 1 Present address: Department of Functional Genomics, Janssen Research Foundation, Beerse, Belgium. modeling in transgenic mice. We have generated transgenic mice that overexpress human ApoE4 (2000. Expression of Human Apolipoprotein E4 in neurons causes hyperphosphorylation of Protein tau in the brains of transgenic mice. Am. J. Pathol. 156 (3) 951±964) or human protein tau (1999. Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am. J. Pathol. 155, 2153±2165) in their neurons. Both develop a similar although not identical axonopathy, with progressive degeneration of nerves and with muscle wasting resulting in motoric problems. Remarkably, ApoE4 transgenic mice are, like the tau transgenic mice, characterized by progressive hyper-phosphorylation of protein tau also in motor neurons which explains the motoric defects. Further crossing with the APP/Lo transgenic mice is ongoing to yield amultipleo transgenic mouse strains to study new aspects of amyloid and tau pathology. q 2000 Elsevier Science Inc. All rights reserved.