O4-01-05: Presenilin 1 mutation promotes Tau phosphorylation and aggregation in a novel Alzheimer's disease mouse model

Abstract

Background: Mutations in the presenilin-1 (PS1) gene increase A production but their effect on tau expression, phosphorylation and/or aggregation has not been thoroughly assessed. Interestingly, patients with PS1 mutations have numerous NFTs suggesting that these mutations sensitize neurons to develop NFTs. An increase in tau phosphorylation has been observed in cells co-transfected with tau and mutant PS1. Also, a complex of PS1, tau and GSK-3 has been observed in human brain. This interaction may regulate tau phosphorylation because GSK-3 has been shown to phosphorylate tau. To investigate the effect of PS1 mutation on tau in vivo, we previously generated a double transgenic model expressing one isoform of wild-type human tau (ON3R) and a mutant form of PS1 (M146L), as well as a triple model that also expresses the Swedish and London mutations in the amyloid precursor protein. The tau pathology in neither models differed from mice expressing only the human ON3R tau isoform (Boutajangout A. et al., Neurobiol. Disease, 15, 47-60, 2004). Methods: To further investigate the potential effect of pathogenic PS1 mutation on tangle formation, we crossed htau mice, that express all 6 human isoforms of tau, with PS1 (M146L) mice. These animals were maintained on a mouse tau knockout background (htau/PS1/mtau-/-). Controls were htau/ mtau-/littermates. The mice were killed at 8-9 months for brain analysis. Results: Levels of total tau did not differ between the groups but PHF1 immunoreactive (IR) soluble tau was increased by 126% (p 0.02) in the htau/PS1/mtau-/mice (n 8) compared to their htau/mtau-/littermates (n 10). Likewise, immunohistochemical analysis revealed an 84% increase in PHF1 IR tau in the pyriform cortex (p 0.02). Analysis of other brain regions, with other tau antibodies as well as of insoluble tau is underway. Furthermore, tau-related pathology and different ages of animals are being assessed. Conclusions: These findings indicate that the M146L PS1 mutation promotes tau phosphorylation and aggregation, suggesting that PS1/tau interaction may be important in the etiology and/or pathogenesis of AD. This novel model can be very useful for studying the onset and progression of AD as well as for therapeutic studies.