Novel high-throughput approaches for the rapid analysis of target engagement by mass spectrometry

Alzheimer's disease (AD) is one of the most common form of neurodegenerative diseases known today, affecting approximately 50 million people worldwide. The pathogenic mechanism is characterised by the formation of toxic A-beta oligomeric species and aggregates that disrupt neuronal function. One of the neuronal cell types most affected by A-beta are glutamatergic neurons, which are required to receive and transmit sensory signals. For example, loss of the sense of smell (olfactory dysfunction) is one of the earliest symptoms of AD in humans. Similarly, in C. elegans, chemosensory deficits in behaviour mediated via glutamatergic neurons, occurs in already young animals expressing A-beta in the nervous system. We however do not know which glutamatergic neuronal subtype loses its signalling activity first as a consequence of A-beta-associated toxicity during AD progression and how neuronal function can be protected.

This project will determine which neuronal circuit succumbs first to A-beta expression during AD progression and how Hsp90 protects glutamatergic neuronal function. Therefore, we will establish an improved C. elegans model of A-beta-associated Alzheimer's Disease (AD) that allows to monitor neuronal signalling activity throughout aging and progression of the disease; using a calcium reporter in combination with a glutamate sensor. The reporter would allow to determine when neuronal signalling activity declines, which neuronal subtypes are affected first and whether protective molecules (such as chaperones and pharmacological compounds) safeguard neuronal signalling activity. Identification of the exact neuronal subtype affected by A-beta expression and how Hsp90 preserves signalling function will provide novel insights into how AD develops. This will facilitate the development of new treatment options that can be applied early in the disease process to delay or even prevent further progression of the disease. The improved C. elegans AD reporter will replace mouse neurodegenerative disease models such as AD, to investigate the protective effects of chaperones and pharmacological compounds at the level of neuronal signalling activity and correlated to behavioural output.