P1-033: Amyloid-induced tauopathy contributes to synaptic and cognitive deficits in a transgenic model for Alzheimer's disease

Abstract

Background: Evaluation of biomarkers and innovative therapies for Alzheimer's disease (AD) suffers from lack of models close to disease progression in human. Most of transgenic models express supraphysiological levels of APP metabolites to mimic AD lesions such as amyloid plaques and neurofibrillary tangles. Our goal was to develop a modelling strategy by gene transfer with two major objectives: (1) create a relevant mouse model closer to human physiopathology, (2) mimic the early stages of AD and thus allowing characterization of early events. We focused on the amyloid cascade and the APP processing to trigger in vivo the production of neurotoxic peptides such as bCTF and Ab42. Methods: We used Adeno-Associated Viruses (AAVs) to express APP (with Swedish and London mutations) and PS1 (M146L mutation). We made a single stereotactic injection in the hippocampus of wild-type mice, followed by behavioral, biochemical and histological analysis. Results: Our strategy allows expression of human APP and PS1 and leads to bAPP production and its neurotoxic catabolites such as sAPPb, bCTF, Ab38, Ab40 and Ab42, as soon as one month post-injection. This production was stable during at least 12 months, without senile plaque formation. Interestingly, only co-injection of APP and PS1 increased the ratio Ab42/Ab40 and triggered hyperphosphorylation of the murine Tau protein which was correlated with increased levels of GSK3b. We also demonstrated a decrease of Beclin1 and NEP specifically observed in AD patient's brain. Finally, significant behavior impairments (Morris Water Maze and Openfield) appeared from 2.5 months after injection. Conclusions: This strategy induced amyloid pathology within the first month post-injection and overcame two major pitfalls of transgenic models, i.e. continuous expression of transgenes from in utero and limitations to the transfer to other species. Stable and more physiological amount of neurotoxic peptides derived from APP was produced and brought out an early link between the APP processing and Tau pathway.