Tau, a molecular modulator of neuronal energy managment

Introduction

The intraneuronal somatodendritic "missorting" and aggregation of Tau are pathological hallmarks in neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), and are thought to be drivers of neurotoxicity.

Overlooked Manifestations

That NDDs manifesting with Tau "missorting" present with (neuro)metabolic abnormalities, often prior to pathology onset, is largely overlooked.

Research Focus

EnergizeTau investigates the groundbreaking new idea that the somatodendritic re-sorting of Tau is a physiological response to bioenergetic challenges faced by excitatory neurons, such as hyperexcitation or energy deprivation.

Role of Tau

In its proposed role as a modulator of neuronal energy management, Tau modulates the cellular energy demand through molecular interactions with key cellular functions, including:

1. Synaptic activity
2. ATP production
3. Protein translation

This modulation alters the neuronal metabolism. Continued energetic stress in disease results in irreversible "silencing" and Tau aggregation in affected neurons.

Methodology

Using my uniquely broad Tau expertise, we decipher how Tau interferes with energy-demanding cellular functions to modulate neuronal energy household downstream of bioenergetic stress.

Experimental Techniques

• Light-induced Tau expression and CRISPR-edited human neurons enable the study of Tau's molecular actions through interactomics and single-molecule imaging, and the effects on cellular functions.
• Tau's influence on neuronal metabolism is determined by longitudinal live cell metabolite imaging and spatial transcriptomics in human brains.
• The impact on gene and chromatin regulation is assessed by Cut&Tag and DNA-FISH.
• Whether stressors converge on energy limitation as a driver of Tau re-sorting is evaluated by high-content metabolite imaging.

Conclusion

EnergizeTau introduces the metabolic component of Tau (patho)biology and generates a paradigm shift in NDD research. It creates space for re-thinking hallmark protein pathology in NDDs and has the potential to result in new approaches targeting neuronal energy metabolism to prevent and treat NDDs.