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

Descrizione del progetto

Interazione cellulare e molecolare nel morbo di Alzheimer

Il morbo di Alzheimer è una forma comune di demenza associata a neuroinfiammazione e perdita di sinapsi neuronali. Per funzionare correttamente, i neuroni necessitano di microtubuli, una rete di strutture a base proteica, ​​che agevolano lo spostamento di sostanze e organuli. Al centro della formazione dei microtubuli c’è una proteina nota come tau che si ripiega in modo errato nel morbo di Alzheimer portando a perdita di sinapsi. Finanziato dal programma di azioni Marie Skłodowska-Curie, il progetto SynapTau si propone di analizzare il ruolo della microglia, ovvero l’insieme delle cellule immunitarie innate nel sistema nervoso centrale, nella perdita sinaptica mediata dalla tau. In un contesto sperimentale, i ricercatori studieranno il ruolo protettivo di specifiche molecole contro il danno sinaptico, aprendo la strada all’identificazione di bersagli terapeutici per il morbo di Alzheimer.

Obiettivo

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.

Coordinatore

UNIVERSITE D'AIX MARSEILLE
Contribution nette de l'UE
€ 195 914,88
Indirizzo
BOULEVARD CHARLES LIVON 58 LE PHARO
13284 Marseille
Francia

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Regione
Provence-Alpes-Côte d’Azur Provence-Alpes-Côte d’Azur Bouches-du-Rhône
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
Nessun dato