Do changes in membrane lipids and neurotransmitter release contribute to age-related memory loss?

Ageing is a major risk factor for a range of debilitating CNS diseases, including Alzheimer’s disease, for which there is currently no known cure. In the absence of gross pathology the ageing process can still impair learning and memory formation. These deficits represent a change in the ability of nerves cells to communicate with each other. Fundamental to the ability of neurons to communicate effectively is the precisely regulated release of chemical neurotransmitters; a process called exocytosis. Currently, there are no studies that have examined how this process changes with increasing age due to the complexity of the mammalian nervous system, however.

We and others have previously shown that old pond snails show many of the hallmarks of the ageing mammalian nervous system and have optimised the technology for performing these experiments at Brighton and therefore this project is timely and has the potential to be impactful through the identification of novel targets for drug therapy and eventually the next generation of anti-dementia drugs.We and others have previously shown that a pair of nerve cells known as the CGCs is vital for learning and memory formation. As the snails age CGC excitability declines and both neuronal communication and the animal’s ability to learn and remember is impaired.Neurotransmitters are stored in vesicles and the process of exocytosis requires the fusion of vesicular lipids with the lipids of the neuronal membrane. This requires complex bending of the lipid membrane which is dependent on the correct membrane lipids. This study will examine the involvement of age-related changes in CGC membrane lipid composition to changes in transmitter release.

This work will be performed in collaboration with Professor Ewing at the University of Gothenburg, Sweden. Professor Ewing has developed a sensitive assay for imaging membrane lipids in single nerve cells; however, this project will be the first to relate these changes to alterations in learning and memory formation. Previous studies have shown that medicines that are routinely used to treat human disease can alter membrane lipid composition and we will examine the ability of one of these, fluoxetine (Prozac), a drug that has previously been shown to reverse age-related memory loss in Lymnaea, to restore normal neurotransmitter release.

Given that membrane lipid composition can also be altered by dietary interventions we will also manipulate the snail’s diet and examine the effects on membrane lipid composition and the animals’ ability to learn and remember. Both interventions have the ability to move rapidly into human dementia trials as their safety in humans is already validated.

This funding will provide a unique opportunity for a student to study at the chemistry-biology interface and area of strength and focus for the newly formed Centre for Stress and Age-Related Disease. The student will also have the opportunity to study for up to 12 months in Sweden with one of the world’s leading analytical chemists.

The work in Sweden will most likely take part in year 2 of the Ph.D. This work will focus on utilising state-of-the-art techniques for monitoring exocytosis, including intracellular electrochemical detectors and electrochemical cytometry to measure vesicular content and submicrometer mass spectrometry (ToF SIMS) imaging for quantifying membrane lipids in both the vesicular and plasma membrane from single CGCs