Objective
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.
Keywords
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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(opens in new window) ERC-2025-STG
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81675 Muenchen
Germany
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