The Mechanisms of neuronal silencing in Alzheimer’s Disease – investigation of cellular and network mechanisms in mouse models of β-amyloidosis | MONSil-AD | Projet | Fiche descriptive | HORIZON | CORDIS

Description du projet

L’inhibition neuronale dans la maladie d’Alzheimer

La maladie d’Alzheimer (MA) se caractérise par de profondes perturbations de l’activité neuronale et de la communication entre les cellules du cerveau. Les premiers stades de la maladie sont marqués par une hyperactivité neuronale, tandis que les stades ultérieurs présentent une inhibition neuronale généralisée. Bien que ce phénomène contribue au déclin cognitif, il reste mal compris. Le projet MONSil-AD, financé par le CER, vise à découvrir les mécanismes à l’origine de l’inhibition neuronale dans la MA. Les chercheurs étudieront trois causes possibles: la perte de connexions entre les neurones, l’accumulation nocive de la protéine tau à l’intérieur des cellules, et la signalisation immunitaire dans le cerveau. En utilisant l’imagerie cérébrale avancée dans des modèles de souris, MONSil-AD entend révéler comment ces processus interagissent, ouvrant ainsi la voie à des stratégies de dépistage et de traitement basées sur l’activité neuronale.

Objectif

Alzheimer’s disease (AD) is defined by pathological brain changes, including the accumulation of β-amyloid and tau deposits over decades. In addition, data in human patients and rodent models indicate that neuronal dysfunctions, i.e. altered action potential firing rates, are further hallmarks of AD. Two forms of neuronal dysfunctions exist - neuronal hyperactivity at early stages, followed later by neuronal silencing. The causes of neuronal hyperactivity have been widely studied. However, the mechanisms of neuronal silencing are still incompletely understood, likely due to the high complexity of interdependent brain changes in late AD stages.
MONSil-AD aims to unravel the multifactorial pathways leading to neuronal silencing in AD mouse models. My preliminary data indicate that silencing co-occurs with emergent tauopathy, loss of dendritic spines, and decreased presynaptic inputs in mouse models of β-amyloidosis. Moreover, the soluble ectodomain of the microglial ‘triggering receptor expressed on myeloid cells 2’ (sTREM2), which is upregulated in AD, suppresses neuronal activity. Based on these findings, I will investigate whether synaptic uncoupling from the circuit causes the silencing of individual neurons (aim 1) and test if intracellular tau accumulation silences neurons on a cellular level (aim 2). In addition, I will explore the contribution of sTREM2 to neuronal silencing in AD (aim 3) and the interactions between the three mechanisms.
To reach the ambitious aims of MONSil-AD, I have implemented cutting-edge in vivo two-photon imaging techniques and developed specialized protocols enabling me, for the first time, to provide a comprehensive picture of the mechanisms leading to neuronal silencing in AD. In addition, MONSil-AD may have direct clinical implications as a basis for the development of an activity-based screening tool for the early non-invasive detection of AD and the development of targeted treatment strategies to prevent neuronal silencing.