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Research on Alzheimer's disease

last modified Jan 28, 2014 02:49 PM

The Laser Analytics Group is working to gain a better understanding of the mechanisms underlying Alzheimer's disease. This is urgently required if new treatments are to be developed.

The progression of Alzheimer's disease (AD), a grave neurodegenerative illness, is associated with the aggregation of a protein called beta-Amyloid protein, which forms the main component of plaques found in the brain of patients suffering the disease. 

It is thought, however, that the neurotoxic function of beta-Amyloid (a-Beta) occurs long before plaques appear: small oligomers of a-Beta are thought to interfere with vital processes in neurons, preventing them from functioning normally. Research into molecular mechanisms of AD and potential therapeutic agents has been severely hampered, however, because it has not been possible so far to study the aggregation process and the resulting structure and morphology of beta-Amyloid in-situ, in the cells where aggregation occurs. 

The challenge is formidable because the oligomers are very small structures, with a lengthscale of about 10 nm, far below what could be imaged with light microscopy, which is limited by optical diffraction to a resolution of around 300 nm. Electron microscopy and atomic force microscopy have the necessary resolution, but they cannot be used to probe in the cell. 

The Laser Analytics group has been able, for the first time, to visualise the morphology and size of oligomer species of a-Beta, in the native environment, using all-optical techniques. This was achieved through application of a so-called "Optical Super-Resolution" technique, which circumvents the problem of optical diffraction and provides an effective resolution down to the 10 nm scale. The results are published in the latest issue of JACS [1]. The work is part of a collaborative effort within the Cambridge Neurodegenerative Disease Consortium, funded by the Wellcome Trust / MRC, to look into the molecular mechanisms of Alzheimer's disease [2].

[1] G.S. Kaminski Schierle et. al (dx.doi.org/10.1021/ja201651w | J. Am. Chem. Soc. 2011, 133, 12902-12905).
[2] www.wellcome.ac.uk/neurodegen

 

Image: 

Centre (grey) a differential interference contrast (DIC) image shows a cultured neuronal cell. Conventional fluorescence images (small red panels) indicate the existence of protein aggregates, but give no information on their size or morphology. Super-resolution images (top panels) clearly reveal the sharp fibrillar morphology of these protein aggregates, and reveal differences between structures found in the intra- and extracellular spaces, suggesting potential mechanisms for their growth and propagation. The molecular structure of a beta-Amyloid protein is illustrated, together with a stacking sequence by which it can form fibrils, in the lower part of the Figure.