Amyloid: Little proteins, big clues

Abstract

, a group of prominent researchers from around the world met in Scotland to discuss a disease that afflicted sheep and goats. Scrapie, as they called it, was important for more than agricultural reasons-it was also the most easily studied example of an emerging class of diseases that destroyed the brain. The illnesses jumped infectiously from animal to animal, yet yielded no trace of a virus or other microorganism. One big clue was that these diseases left behind insoluble clumps, or plaques, made from millions of tiny fibrils, each of which comprised hundreds or thousands of proteins. A striking new hypothesis proposed that these fibrils and their plaques marked the toxic passage of infectious proteinaceous particles, or prions. On the first night of the conference, several researchers gathered for dinner. Among them were Colin Masters, a neuropathologist from the University of Western Australia, and Konrad Beyreuther, a protein-sequencing expert from the University of Cologne in Germany. Masters began telling Beyreuther about a human disease that featured plaques like those seen in scrapie and seemed to be very common. It was called Alzheimer's disease. "Until then I had never heard of Alzheimer's disease, " Beyreuther recalls.

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

“…Therefore, for AD patients, impaired Aß clearance could be mainly due to decreased degradation of Aβ monomers and oligomers, whereas, for aged APP/PS1 mice, it is primarily attributed to reduced degradation of Aβ polymers and fibers. It is known that Aβ monomers and oligomers are the main components of neurotoxic substances in the brain, and the toxicity of amyloid plaques is relatively weak (Schnabel 2011). Therefore, we speculate that decreased IDE, but not NEP impairment, may be another key factor for the increased survival time of APP/PS1 mice when compared with patients with AD.…”

Can Parkinson's disease pathology be propagated from one neuron to another?

“…This coupling between amyloid plaque distribution and symptomatic progression led researchers nearly three decades ago to first hypothesize that a prion-like mechanism was involved in AD (reviewed by Schnabel, 2011). The distribution of amyloid plaques in the AD brain at different disease stages has also been described by Braak and colleagues (Braak et al, 1993).…”

Proliferation of amyloid-β42 aggregates occurs through a secondary nucleation mechanism

“…Particular attention has been devoted to the study of oligomers, which are small multimers that do not yet possess the ability to elongate at the same rate as fibrils and are commonly associated with neuronal death both in vivo and in vitro (2,(7)(8)(9). The relationship between low molecular weight toxic oligomers and the mature fibrils has remained elusive, with some studies suggesting that oligomers are generated predominantly as on-pathway intermediates in fibril formation and others indicating that these different species originate mainly from independent pathways (13). Here, we connect the characteristic macroscopic features of Aβ42 fibril formation to their microscopic determinants through the analysis of experimental kinetic data in terms of microscopic rate laws and use selective radiolabeling, size-exclusion chromatography, and cell viability studies to define the origin of the toxic oligomers and their relationship with fibrillar aggregates.…”