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

Descrizione del progetto

Silenziamento neuronale nella malattia di Alzheimer

La malattia di Alzheimer è caratterizzata da profondi disturbi nell’attività neuronale e nel modo in cui le cellule cerebrali comunicano. Le fasi iniziali della malattia sono caratterizzate da iperattività neuronale, mentre quelle successive mostrano un diffuso silenziamento neuronale. Sebbene questo silenziamento contribuisca al declino cognitivo, è ancora poco conosciuto. Il progetto MONSil-AD, finanziato dal CER, si propone di scoprire i meccanismi che determinano il silenziamento neuronale nella malattia di Alzheimer. I ricercatori studieranno tre possibili cause: la perdita di connessioni tra i neuroni, l’accumulo dannoso della proteina tau all’interno delle cellule e la segnalazione immunitaria nel cervello. Usando immagini cerebrali avanzate in modelli murini, MONSil-AD si propone di rivelare come questi processi interagiscono, aprendo la strada a strategie di screening e trattamento basate sull’attività neuronale.

Obiettivo

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.