The beta-amyloid peptides attack and breakdown connections between neurons and aggregate further to form ‘senile plaques’ brain deposits that characterise Alzheimer’s disease. This synaptotoxic property of beta-amyloid underlies memory impairment and ‘drives’ other Alzheimer’s disease neuropathologies.
The protein alpha-synuclein misfolds to form fibrils that are toxic to synapses and aggregates further to form deposits inside nerve cells known as Lewy bodies that characterise Parkinson’s disease and Dementia with Lewy bodies.
Alzheimer’s and the Lewy body diseases comprise the majority of neurodegenerative disease cases. Although viewed as separate disease entities there is growing awareness that considerable overlap exists in their clinical and neuropathological features.
We made a fundamental observation. We found that beta-amyloid acts through alpha-synuclein to attack synapses. If we silence the alpha-synuclein gene the synaptotoxic effects of beta-amyloid no longer manifest: Without alpha-synuclein beta-amyloid is harmless!
We have uncovered considerable detail of the molecular signalling pathway through which beta-amyloid attacks synapses. We now have pilot data showing that the toxic forms of alpha-synuclein act via this same pathway. The project we offer focuses on elucidating exactly where alpha-synuclein sits, and how it acts, within the “beta-amyloid synaptotoxic pathway”.
This project will complement, and benefit in many ways, from the ongoing work around beta-amyloid and alpha-synuclein within the group. It will utilise a range of molecular and cellular biology techniques and several state-of-the art super-resolution imaging instruments and techniques. By year 2 (Y2) the position of alpha-syn will be determined, in Y3 how beta-amyloid acts upon it and by Y4 how alpha-syn acts on downstream elements of the pathway.
Only by gaining a better understanding of where and how alpha-synuclein acts, and interrelationship between with beta-amyloid will we better understand the disease processes and be able to identify effective targets to which truly disease modifying drugs can be developed.