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Synaptic resilience in Tau-induced neurodegeneration

Project description

Finding therapeutic targets to fight Tau-induced neurodegeneration

Tauopathies represent a group of progressive neurodegenerative disorders that are characterised by the presence of Tau protein aggregates in the brain and by the absence of disease-modifying therapies. Remarkably, when hamsters and squirrels enter hibernation, they also display Tau pathology and synaptic loss, which are reversible, in contrast to progressive in the case of human dementia. The EU funded Hibernating_Synapses project aims to uncover the mechanisms of synaptic remodelling in the case of hibernation and explore the pathways that reverse synapse loss as a tool to counteract Tau induced synaptic decline in tauopathies. The project will identify the drivers of synaptic remodelling during hibernation and the human homologues of the hamster genes that reverse synaptic loss in the attempt to find the pathways rescuing Tau-induced neurodegeneration.

Objective

Dementia is an enormous burden on society. Patients require life-long care and there is no cure or symptomatic treatment. At early phases, dementia is closely associated with synaptic degeneration and this correlates well with Tau pathology in >20 Tauopathies. Interestingly, historic observations in hamsters and squirrels show that when they enter into hibernation, they also display Tau pathology and synaptic loss. Pathologists have pointed to these similarities; however, there is an important difference: synaptic loss is progressive in dementia, but reversible in hibernating animals. Capitalizing on recent technological advancements, I will unravel the mechanisms of this remarkable, yet understudied process of synaptic remodeling in hibernation and then use the pathways that reverse synapse loss in hamsters, to counteract Tau-induced synaptic decline in models of dementia. We will achieve these goals by first defining and studying the molecular and cellular drivers of synaptic remodeling during cycles of hibernation. This is based on innovative spatial transcriptomic and synaptic proteome analyses in hamster brains. We will then identify the human homologues of the hamster genes that reverse synaptic loss following hibernation and use a selection strategy in xenotransplanted human neurons and functional assays on custom-designed multielectrode arrays, to isolate genes rescuing Tau-induced neurodegeneration. This approach is bold, but feasible; my lab has a record of accomplishment in synaptic and neurodegeneration research and we already have strong preliminary work implicating specific pre-synaptic pathways in the types of Tau-dependent synaptic remodeling that we will study here. The gain is that we will uncover the mechanisms of a remarkable process of synaptic resilience, and apply this to rescue the synaptic loss in neurodegeneration. This project will define a conceptually new and unexplored class of therapeutic targets to tackle Tau-induced neuronal decline.

Host institution

VIB VZW
Net EU contribution
€ 2 500 000,00
Address
SUZANNE TASSIERSTRAAT 1
9052 ZWIJNAARDE - GENT
Belgium

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Region
Vlaams Gewest Prov. Oost-Vlaanderen Arr. Gent
Activity type
Research Organisations
Links
Total cost
€ 2 500 000,00

Beneficiaries (1)