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Watching molecules grow helps find origin of Alzheimer's

One in three people in the UK know a family member or friend with dementia and the number of people suffering from this life shattering disease is rising rapidly as our population ages. Researchers at the University of Cambridge are developing super-resolution microscopes to watch the earliest steps in the progression of the disease at never before seen detail.

It has been known since the discovery of Alzheimer's Disease in the 19th century that people with the condition have abnormally high levels of sticky protein clumps, or ‘amyloid plaques’, in their brains. These plaques interfere with the healthy neurons that carry messages in our brains and gradually destroy them, leading to dementia. Considerable effort has been made to develop drugs to break down plaques with the hope that this would stop the damage, but every attempt to do this has failed so far and in several cases made symptoms worse. Even drugs approved for use only provide a slight lessening of cognitive decline.

The brutal failure rate of these therapies has forced scientists to take a step back and reconsider the causes of the disease at the nanoscale. Scientists now believe that a toxic soup of amyloid fragments could be the real cause. These fragments are made up of naturally occurring proteins which misfold and stick together, or aggregate, and go on to form thin filamentous structures called amyloid fibrils which are one of the main components of plaques. Although we don't know why these early fragments are harmful to neurons, if we can understand how they form and how they interact with different molecules it could help find new ways of interfering with this seemingly unstoppable chain reaction .

Until recently the only way of looking at the tiny aggregates was to use electron microscopy which requires samples to be frozen and can't be used to watch live cells in real-time. Light microscopy is widely used by scientists to study dynamic biological processes but for over a century it was believed there was an unbreakable limit on the size of the objects that could be seen. Due to the diffraction of light, anything smaller than about 200 nm  appears as a blurry spot. For this reason it was impossible to distinguish between neighbouring nanoscale aggregates using light microscopy.

Thanks to recent breakthroughs, the diffraction limit has now been circumvented giving rise to so-called super-resolution microscopy, earning its inventors the 2014 Nobel Prize for Chemistry. One of the techniques, called STORM, allows imaging with nanometre resolution by causing dye molecules attached to the structures to blink on and off. In standard light microscopy, the light emitted from these dyes overlaps and any detail is lost but switching most of the dyes off means that the few that are left on can be pinpointed with nanometre precision. Combining thousands of these localisations builds up an image with ten times higher resolution, allowing the structure of nanoscale amyloid aggregates to be imaged under physiological conditions.

Another technique I am developing within the Laser Analytics Group in the Department of Chemical Engineering and Biotechnology is conceptually very different. This technique, called structured illumination microscopy (SIM), doesn't require the dye molecules in the sample to blink, but instead excites them using patterned excitation light. The  zigzags of the excitation light mixes with the edges in the sample  structure to produce beat patterns, a phenomenon commonly seen on TV when someone wears a striped shirt: Moiré fringes appear due to overlapping of the stripes with the regular pattern of a digital camera's pixels. In SIM, these patterns  can encode high resolution information that would normally be unobservable due to the diffraction limit. The advantage of SIM over localisation based techniques is that it is practically instantaneous, allowing us to image aggregates as they move around inside living cells .

Super-resolution microscopy is opening up a new chapter in the study of amyloid self assembly and I hope that it helps us understand why they have such devastating effects in Alzheimer's disease.

Laurie Young

Laser Analytics Group, Chemical Engineering and Biotechnology

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