[P4-037]: Identification of novel targets for inhibiting prion-like seeding and propagation of Tau pathology in vitro and in vivo

Abstract

Background: Positive allosteric modulators of AMPA receptors (AMPA-PAMs) are small molecules that keep the AMPA receptor in an active state by decreasing deactivation or desensitization. They have been proposed to treat cognitive decline in dementias and Alzheimer disease (AD). S 47445 is a novel AMPA-PAM. Here, the mechanisms by which S 47445 could improve synaptic strengthen and connectivity were studied and compared between young (3-months old) and middle-aged freely moving mice (14-months old). Methods: LTP was evoked at the CA3-CA1 synapse using high-frequency stimulation (HFS) protocol at two occasions on day 1 and on day 13 after the first administration of S 47445 (3mg/kg or 10mg/kg). Assessment of drug effect on LTP was performed after either acute or chronic treatment. The drug effect on micro-cytoarchitecture in hippocampal (CA1 and CA3) and cortical tissue (L2-3 and L5-6) was also evaluated by confocal mi-croscopy by assessing number and size of positive particles for the presynaptic vesicular glutamate transporter VGlut1 and the post-synaptic protein spinophilin. Results: Middle-aged control mice displayed a marked significant deficit of LTP as compared to young control mice following the first presentation of the HFS protocol. After acute administration of S 47445 at 10mg/kg in middle-aged mice, a complete reversion of the LTP deficit was observed on day 1. Then, chronic treatment with S 47445 at 10mg/kg in middle aged animals significantly counteracted the aged deficit of LTP. During the second HFS presentation, LTP was much smaller than during the previous acute experiment in each mice group, suggesting a loss of LTP-evoked phenomenon. Interestingly, the chronic administration of S 47445 at 10mg/kg in middle-aged mice induced significantly larger LTP values as compared to young control and middle-aged control mice. Moreover, chronic treatment with S 47445 at 10mg/kg significantly prevented the decrease in number and size of VGlut1 and spinophilin in CA1-CA3 and in the cortex of middle-aged mice. Conclusions: Collectively, by its different effects observed, S 47445 is able to modulate both the structure and function of hippocampal excitatory synapses known to be involved in learning and memory processes and could provide beneficial effects in dementias such as AD. Background: In AD, Tau pathology progresses in a stereotypic spatiotemporal pattern, strongly correlating with progression of disease symptoms. Prion-like propagation of Tau-pathology, or propagation of Tau-misfolding between cells and functionally connected brain regions, provides a compelling mechanism for this ste-reotypic progression of Tau-pathology, and hence an attractive therapeutic target. Methods: To test and validate novel therapeutic targets capable of inhibiting prion-like progression of Tau-pathology , we have generated combined in vitro and in vivo models reca-pitulating prion-like seeding and propagation of Tau-pathology. Seeding of pre-aggregated Tau in Tau expressing primary neurons and Tau transgenic mice recapitultes strong induction of Tau-pathology and propagation to the contralateral side. Results: Using these models we have analysed and evaluated the modifying potential of different targets on Tau pathology and propagation of Tau pathology. Targets under evaluation encompass Tau-interactome based Tau interacting proteins, including OTUB1 and other identified Tau-interacting proteins, as well as hypothesis based analysis. Within this analysis we identified OTUB1 as Tau deubiquitinase, involved in the accumulation of pathological forms of Tau. We furthermore identified novel targets with modifying effect on prion-like seeding and propagation of Tau-pathology. Conclusions: We here present the identification of different targets with a modu-latory effect in vitro and in vivo on Tau-pathology and prion-like propagation of Tau-pathology.