Why did we fund this project?
This award aims to use a C. elegans model, as a replacement for rodent models, to investigate glutamatergic neuronal signalling in Alzheimer’s disease.
Glutamatergic neurons are one of the cell types most affected by toxic build-up of the amyloid beta aggregates that disrupt neuronal function in Alzheimer’s Disease. However, it is not known which of the sensory neuronal systems loses function first as a result of disease progression or how neuronal function can be protected. Transgenic animal models, particularly rodents, are often used to study Alzheimer’s disease. These animals have severe atrophy of the brain and humane endpoints are used to prevent unnecessary suffering. C elegans has the potential to be used as an alternative model as animals display deficits in behaviours associated with glutamatergic neurons when amyloid beta is expressed in neurons.
The student will demonstrate the replacement potential of transgenic C elegans by generating lines with calcium reporters, in combination with a glutamate sensor, as new tools for the community to use. The reporter lines will enable neuronal signalling to be monitored non-invasively throughout amyloid accumulation. The student will use these new lines to determine the role of heat shock protein 90, which is thought to provide neuronal protection and preserve signalling function. They will develop skills in fluorescent imaging, behavioural assays and proteomic studies.
This award was made as part of the 2019 highlight notice fostering collaborations between researchers who use mammalian models and those that use species not protected by laboratory animal legislation, such as C.elegans.
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 Aβ oligomeric species and aggregates, that disrupt neuronal function. One of the neuronal cell types most affected by Aβ 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 Aβ in the nervous system. We however do not know which glutamatergic neuronal subtype loses its signalling activity first as a consequence of Aβ-associated toxicity during AD progression and how neuronal function can be protected.
Using a C. elegans model of AD, we have shown that increased expression of the molecular chaperone Hsp90 in the C. elegans nervous system has two effects. Firstly, our preliminary data shows that Hsp90 cell-autonomously protects neurons against the toxic effects of neuronally expressed Aβ(1-42) by suppressing the chemosensory behavioural deficit. Secondly, it cell - non-autonomously activates Hsp90 expression in other cell types via transcellular chaperone signalling (TCS), and so suppresses the formation of Aβ aggregates in distal cells. We found that neuron-induced TCS depends on glutamatergic neurotransmission. This is interesting, because Hsp90 is also known to regulate glutamate receptor function and neurotransmitter release. What we don’t know is whether this regulatory role of Hsp90 also extends to AD, by safeguarding glutamatergic neuronal signalling function during AD progression; and whether TCS can be harnessed to induce protective Hsp90 from one glutamatergic neuronal cell type to another.
We now want to determine which neuronal circuit succumbs first to Aβ expression during AD progression and how Hsp90 protects glutamatergic neuronal function. Therefore, we will establish an improved C. elegans model of Aβ-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 Aβ 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.