We have reported transgenic mice with neuronal overexpression of the clinical mutant ϐ-amyloid precursor protein (APP) known as London, which develop an AD-related phenotype [Moechers, Dewachter, Lorent, Reversé, Baekelandt, Nadiu, Tesseur, Spittaels, Van den Haute, Checler, et al. (1999) J. Biol. Chem. 274, 6483-6492]. Characterized early symptoms (3-9 months) include disturbed behaviour, neophobia, aggression, hypersensitivity to kainic acid, hyposensitivity to N-methyl-D-aspartate, defective cognition and memory, and decreased long-term potentiation. Late in life, at 12-15 months, amyloid plaques develop in the brain and correlate with increased levels of ϐ-amyloid (Aϐ)40/42 (the 40- and 42-amino-acid forms of Aϐ). The formation of amyloid plaques is dissociated in time from and not involved in the early phenotype. Hyperphosphorylated protein tau is present but no tangle pathology is observed. In double-transgenic mice, i.e. APP/London x Presenilin 1, the increased production of Aϐ results in amyloid plaques developing by the age of 6 months. Transgenic mice with overexpression of either human apolipoprotein E4 (ApoE4) or human protein tau in central neurons develop severe axonopathy in the brain and spinal cord. Progressive degeneration of nerves and muscles is demonstrated by motor problems, wasting and premature death. Tau is hyperphosphorylated but there is no formation of filaments or neurofibrillary tangles. The tangle aspect of AD pathology is still missing from all current transgenic amyloid models. Its implementation will require insight into the cellular signalling pathways which regulate the microtubule-stabilizing function by phosphorylation of neuronal tau.
Modelling Alzheimer's disease in multiple transgenic mice
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Cora O'Neill, Brian Anderton, Ilse Dewachter, Dieder Moechars, Jo van Dorpe, Ina Tesseur, Chris Van den Haute, Kurt Spittaels, Fred Van Leuven; Modelling Alzheimer's disease in multiple transgenic mice. Biochem Soc Symp 1 February 2001; 67 203–210. doi: https://doi.org/10.1042/bss0670203
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