The overall aim of SynapTau was to evaluate the contribution of microglia on tau-mediated synaptic loss in Alzheimer’s disease (AD), based on functional and structural synaptosomal changes, which may provide clues for developing original therapeutic strategies against a hitherto incurable disease. Determining the impact of tau accumulation on synaptic loss is critical, especially considering that synaptic dysfunction is an early key pathological event that correlates with cognitive decline in AD. Beyond tau and amyloid-β (Aβ) pathologies, neuroinflammation and gliosis are also hallmarks of the AD brain and are thought to play a pivotal role on synaptic loss. Accordingly, microglia depletion strongly attenuates tau-mediated neurodegeneration and synaptic loss . Despite the link between tau, synapses and inflammation in AD, we do not yet understand the specific interactions between synaptic proteins, glia and pathological tau that lead to synaptic loss. Therefore, my objective was to provide a better understanding of the role of microglia in tau-mediated synaptic loss based on my longstanding experience on the topic and on recent observations I made in the P301S mouse model of AD/tauopathy depleted for microglia. In a pilot study, I explored synaptosomes containing glial processes in close proximity to synapses to identify changes resulting from microglia depletion that account for synaptic protection against tau pathology. Two main original observations from this pilot study set the basis of SynapTau project: i) The upregulation of UCH-L1, an enzyme required for normal synaptic function; ii) Most of theupregulated proteins in the synaptosomes of microglia depleted-P301S mice are normally expressed by astrocytes.
Therefore, in SynapTau, I proposed to study potential protective mechanisms against tau-mediated synaptotoxicity set in motion by microglial depletion that target neurons (objective 1) and neuron/astrocyte interactions (objective 2). In objective 1, I hypothesize that enhancing UCH-L1 expression in neurons will protect against tau-mediated synaptic damages. In objective 2, I hypothesize that neuron-glia interactions are modified after microglia depletion, with changes in the formation and function of perisynaptic astrocytic processes that may support beneficial pathological outcomes. SynapTau is a highly significant project as it aims to discover new therapeutic targets to maintain synaptic integrity and function to slow down AD neurodegeneration and cognitive decline.
I was expecting to provide a better understanding of the interplay between tau pathology, gliosis and synaptic alterations in AD through in-depth proteomic, behavioral, electrophysiological, biochemical and brain imaging approaches. Moreover, this project will be an asset in obtaining a permanent position and becoming an independent researcher. Indeed, I obtained an ATIP-Avenir grant to start my own research lab, which began in January 2023 and was not compatible with my MSCA grant. For this reason, I had to terminate my MSCA grant on the 31st of December 2022.
