Synaptic resilience in Tau-induced neurodegeneration

Introduction

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 over 20 Tauopathies.

Observations in Hibernation

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.
• Synaptic loss is reversible in hibernating animals.

Research Objectives

Capitalizing on recent technological advancements, I will unravel the mechanisms of this remarkable, yet understudied process of synaptic remodeling in hibernation. I will then use the pathways that reverse synapse loss in hamsters to counteract Tau-induced synaptic decline in models of dementia.

Methodology

We will achieve these goals by:

1. 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.
2. Identifying the human homologues of the hamster genes that reverse synaptic loss following hibernation.
3. Using a selection strategy in xenotransplanted human neurons and functional assays on custom-designed multielectrode arrays to isolate genes rescuing Tau-induced neurodegeneration.

Feasibility and Impact

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.

Conclusion

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.