16 September 2009

Research into Amyloid β-protein

A different look at Amyloid β-protein
Dementia News (Alzheimer’s Australia): 4 September 2009
One of the pathologies thought to be associated with the development of Alzheimer’s disease is the formation of plaques made up of Amyloid β-protein. But recent research suggests that the immediate damage to brain cells, and their eventual death, may be caused by neurotoxic (harmful to brain cells) oligomers (oligomers are clusters of limited numbers of monomers, which are simple molecules that can combine with identical or similar molecules) of Amyloid β-protein in Alzheimer's disease rather than the Amyloid β-protein plaques. These oligomers vary in size: some have two molecules, some three, and some four.

Drs Ono, Condron and Teplow from the School of Medicine at the University of California-Los Angeles, created various sizes of Amyloid β oligomers in the laboratory, each size matching one the forms found in the brains of people with Alzheimer’s disease. Once created, the oligomers were studied in various ways (CD spectroscopy, Thioflavin T fluorescence, EM, atomic force microscopy, and neurotoxicity assays) to determine their levels of neurotoxicity.

The researchers found that levels of toxicity increase dramatically with increases in the size of oligomers from two to three to four Amyloid β molecules. But, the increases in levels of toxicity were not linear. In other words, although it would be reasonable to expect that two molecules would be twice as toxic as one, they are in fact three times more toxic than one, and oligomers containing three or four Amyloid β molecules are more than ten times more toxic than one. But, although larger oligomers have greater neurotoxicity than smaller ones, they are fairly rare in the brains of people with Alzheimer’s disease.

The researchers suggest that the accumulative effect of the greater numbers of small oligomers is likely to be equivalent to, or even greater than, the effects of the larger oligomers. The researchers state that their findings significantly extend our understanding of the dynamics, structure, and relative neurotoxicity of pure Amyloid β oligomers. This could have important implications for the development of treatments that target these harmful oligomers.

Reference: Ono K, Condron M, and Teplow D. 2009. Structure– neurotoxicity relationships of amyloid β-protein oligomers. Proceedings of the National Academy of Sciences, published online before print August 12, 2009, doi:10.1073/pnas.0905127106.

See related Alzheimer's News story: UCLA researchers determine toxicity levels of Alzheimer's clusters in brain

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