Study in Nature Chemistry also elucidated the process of Aß42 aggregation.
A cluster of 12 peptides in amyloid beta (Aß) 42 may be the toxic agent in Alzheimer’s disease, according to a team from the University of California, Santa Barbara. They report on the process by which the toxic Aß42 peptides aggregate and the finding of this dodecamer in this week’s Nature Chemistry. The paper is called “Amyloid-ß protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer’s disease.”
The Aß42 peptide is composed of 42 amino acid residues and is clipped from a much larger protein, the amyloid precursor protein (APP). A second peptide, Aß40, is 10 times more abundant than Aß40 in healthy human brains and is also clipped from APP. It is identical to Aß42 except that it is missing the last two amino acids.
Aß42 never grows beyond a tetramer (a cluster of four units) and therefore is nontoxic. By contrast Aß42 grows to form rings of six units each. According to the article, two of these rings stack to form a dodecamer, which is made up of 12 units, and then the aggregation stops. These dodecamer clusters are long-lived but may eventually rearrange to form so-called B-sheet structures. These structures in turn lead to the large fibrils that form the plaques found in the brains of those with Alzheimer’s disease and other neurodegenerative diseases.
In related studies, transgenic mice implanted with the gene that expresses human APP (and hence able to form Aß42 in their brains) were found to quickly develop memory deficits as if they have Alzheimer’s disease. The only Aß42 species found in the brains of the mice correlates with the dodecamer of Aß42 characterized in the current study. This implicates the dodecamer of Aß42 as the toxic agent in Alzheimer’s disease, the researchers note.
The research group used ion mobility coupled with mass spectrometry, which allows determination of in vitro oligomer distributions and the qualitative structure of each of the aggregates. This research method is new but is gaining acceptance in the biological community, according to Michael T. Bowers, Ph.D., professor of chemistry and biochemistry and lead scientist of this study.
“In biology, structure and function are tightly coupled,” he said. “When it became clear that small soluble oligomers were most probably the toxic agents in Alzheimer’s disease, I realized our ion mobility methods could contribute, since we could measure the oligomer distribution and shapes of these peptides for the first time.” To fully understand the disease, however, effects of the oligomerization process would have to be observed at the cellular level, Dr. Bowers adds.
