European Commission logo
español español
CORDIS - Resultados de investigaciones de la UE
CORDIS

Targeting the interrelation between microglia, neurons, and astrocytes to counteract tau-mediated synaptic impairments and neurodegeneration in AD.

Descripción del proyecto

Interacción celular y molecular en la enfermedad de Alzheimer

La enfermedad de Alzheimer (EA) es una forma común de demencia asociada a la neuroinflamación y la pérdida de sinapsis neuronales. Para funcionar correctamente, las neuronas necesitan microtúbulos, una red de estructuras basadas en proteínas que facilitan el movimiento de las sustancias y orgánulos. En la formación de los microtúbulos es fundamental una proteína denominada tau que, en la EA, se pliega mal y provoca la pérdida de sinapsis. El objetivo del proyecto SynapTau, financiado por las Acciones Marie Skłodowska-Curie, es analizar minuciosamente el papel de la microglia —las células inmunitarias innatas del sistema nervioso central— en la pérdida sináptica mediada por tau. En un entorno experimental, los investigadores estudiarán el papel protector de moléculas específicas contra el daño sináptico, lo cual allanará el camino a la identificación de dianas terapéuticas para la EA.

Objetivo

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.

Coordinador

UNIVERSITE D'AIX MARSEILLE
Aportación neta de la UEn
€ 195 914,88
Dirección
BOULEVARD CHARLES LIVON 58 LE PHARO
13284 Marseille
Francia

Ver en el mapa

Región
Provence-Alpes-Côte d’Azur Provence-Alpes-Côte d’Azur Bouches-du-Rhône
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
Sin datos