Abeta-mediated toxicity in Alzheimer's disease: delineating mechanisms of internalisation, cell-cell transmission and synaptic dysfunction

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Alzheimer's disease (AD) is a devastating illness that affects 1% of the population. Although some familial forms of AD exist, most Alzheimer's patients suffer from sporadic, late-onset AD, associated with ageing. The causes of Alzheimer's disease remain unclear, although it is now well-established that in brain cells (neurons), abnormal folding of small proteins (called Abeta and tau) represents a pivotal step in disease pathology. Our work aims to understand how these proteins can lead to the deterioration of neuronal function underlying the degenerative symptoms seen in Alzheimer's sufferers. To examine this we will use both artificially-grown and native networks of living neurons and recapitulate the changes occurring at the onset of AD as the target proteins change and become toxic. We will utilise state-of-the-art imaging methods to directly visualise the effects on basic neuronal function. Our research will also examine how the spread of toxic proteins between neurons might underlie the progression of the disease. A specific consequence of AD is the gradual dysfunction of synapses - the sites for neuron-to-neuron signalling - that are essential for the brain's ability to process information. We will use specialised fluorescence markers to examine synaptic signalling events and characterise the specific mechanisms which become disrupted. Finally, we will combine our fluorescence measurements with novel state-of-the-art microscopy experiments, allowing us to examine the detailed structural changes in neurons caused by misfolding proteins at high-resolution. Using this approach, we anticipate major new insights into understanding the critical cellular and molecular changes associated with Alzheimer's disease. With this knowledge, the rational design of therapeutic agents that can target these processes and alleviate or prevent disease symptoms becomes a realistic prospect.