Project description
Cellular and molecular interplay in Alzheimer’s disease
Alzheimer’s disease (AD) is a common form of dementia associated with neuroinflammation and loss of neuronal synapses. To function properly, neurons require microtubules, a network of protein-based structures that facilitate the movement of substances and organelles. Central to the formation of microtubules is a protein known as tau that misfolds in AD and leads to loss of synapses. Funded by the Marie Skłodowska-Curie Actions programme, the SynapTau project aims to dissect the role of microglia – the innate immune cells in the central nervous system – in tau-mediated synaptic loss. In an experimental setting, researchers will study the protective role of specific molecules against synaptic damage, paving the way for identification of therapeutic targets for AD.
Objective
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
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
13284 Marseille
France