The overall aim of SynapTau is to evaluate the contribution of microglia on tau-mediated synaptic loss in Alzheimer’s disease (AD), based on synaptosomal changes, which may help to develop therapeutic strategies against AD. Determining the impact of tau accumulation on synaptic loss is critical since it correlates with cognitive decline in AD. Beyond tau and amyloid-β pathologies, gliosis is also an AD hallmark and is thought to play a pivotal role on 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. My objective is to provide a better understanding of the role of microglia in tau-mediated synaptic loss based on recent observations I made. I recently explored synaptosomes containing glial processes near synapses from microglia depleted P301S mice, a mouse model of tauopathy, to identify changes resulting from microglia depletion that account for synaptic protection against tau pathology. I reported an upregulation of UCH-L1, an enzyme required for normal synaptic function. Moreover, most of the upregulated proteins in the synaptosomes of microglia depleted-P301S mice are expressed by astrocytes. I propose to study potential protective mechanisms against tau-mediated synaptotoxicity set in motion by microglial depletion that target neurons and neuron/astrocyte interactions. 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.
Fields of science
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme