Modeling Alzheimer's disease in transgenic mice: effect of age and of Presenilin1 on amyloid biochemistry and pathology in APP/London mice

In transgenic mice that overexpress mutant Amyloid Precursor Protein [V7171 ], or APP/London (APP/Lo) (1999a. Early phenotypic changes in transgenic mi ce 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 neu rodegeneration and apoptosis. Neuroscience 91, 819-830) the AD related phen otype 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, aggressi on, glutamate excitotoxicity, defective cognition and decreased LTP. The AP P/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 mi ce, brain soluble and especially "insoluble" amyloid peptides dramatically increased, while normalized levels of secreted APPs alpha and APPs beta, as well as cell-bound beta -C-stubs, remained remarkably constant, indicating normal alpha- and beta -secretase processing of APP. In double transgenic mice, i.e. APP/Lo x PS1, clinical mutant PS1[A246E] but not wild-type human PS1 increased A beta, and plaques and vascular amyloid developed at age 6- 9 months. The PS1 mutant caused increasing A beta 42 production, while agei ng did not. Amyloid deposits are thus formed, not by overproduction of A be ta, 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 therapeuti c potential. Although hyper-phosphorylated protein tau was evident in swoll en neurites around the amyloid plaques, neurofibrillary pathology is not ob served and the "tangle" aspect of AD pathology is therefore still missing f rom all current transgenic "amyloid" models. Also the "ApoE4" risk for late onset AD remains a problem for modeling in transgenic mice. We have genera ted transgenic mice that overexpress human ApoE4 (2000. Expression of Human Apolipoprotein E4 in neurons causes hyperphosphorylation of Protein mil in the brains of transgenic mice. Am. J. Pathol. 156 (3) 951-964) or human pr otein tau (1999. Prominent axonopathy in the brain and spinal cord of trans genic mice overexpressing four-repeat human tau protein. Am. J. Pathol. 155 . 2153-2165) in their neurons. Both develop a similar although not identica l axonopathy, with progressive degeneration of nerves and with muscle wasti ng resulting in motoric problems. Remarkably, ApoE4 transgenic mice are, li ke the tau transgenic mice, characterized by progressive hyper-phosphorylat ion of protein tau also in motor neurons which explains the motoric defects . Further crossing with the APP/Lo transgenic mice is ongoing to yield "mul tiple" transgenic mouse strains to study new aspects of amyloid and tau pat hology. (C) 2000 Elsevier Science Inc. All rights reserved.