Abstract
<h3>ABSTRACT</h3> Neurodegenerative diseases, such as Alzheimer’s Disease (AD), are associated with protein misfolding and aggregation into amyloid fibrils. Increasing evidence suggests that soluble, low molecular weight aggregates play a key role in disease-associated toxicity. Within these aggregates, protofibrillar loop-like structures have been observed for a variety of amyloid systems and their presence in brain tissues is associated with high levels of neuropathology. However, their mechanism of formation and relationship with mature fibrils has largely remained challenging to elucidate. Here, we use atomic force microscopy and statistical theory of biopolymers to characterise amyloid ring structures derived from the brains of AD patients. We analyse the bending fluctuations of protofibrils and show that the process of loop formation is governed by the mechanical properties of their chains. We conclude that <i>ex vivo</i> protofibril chains possess greater flexibility than that imparted by hydrogen-bonded networks characteristic of mature amyloid fibrils, such that they are able to form end-to-end connections. Furthermore, we show that these findings can be extended to several amyloid systems, giving a general framework relating the mechanical properties of assemblies and the conditions in which they can form loop structures. These results explain the diversity in the structures formed from protein aggregation and sheds light on the links between early forms of flexible ring-forming aggregates and their role in disease.
Highlights
"We are told, that in scoliosis?which is another great field for therapeutic delusions?" quick results have followed the treatment in every instance, and without employing suspension, casts, braces, or other auxiliary methods." we come to the various " congestive forms of pelvic diseases " in which we are told that vibratory treatment has given results " that may well inspire the hope that a brighter day is soon to dawn in the management of this large and troublesome class of cases." Again "Mechanical vibration has been found uniformly successful in the treatment of varicose conditions*"
Otherwise a form of treatment which, according to Dr Pilgrim and others, is one of considerable utility, may drift, as so many useful things have done, into the hands of the great unqualified, thereby getting soiled with a taint of quackery which it may be very difficult afterwards to get rid of
Summary
Pilgrim,* who is in the full swing of what is going on in New York in regard to psychiatry and electro therapeutics, speaks of this mode of treatment as "the newest and one of the most valuable methods in advanced therapeutics." Mechanical stimulation and vibration have for their aim " the accomplishment of one primary condition, viz., stimulation of the nerve or nerve centres concerned in and controlling the diseased organ, which are found principally in the spinal and sympathetic systems," and he goes on to say that "this is attempted for the double purpose of (1) stimulating and equalising blood currents ; and (2) stimulating secretion and excretion, and the lymphatics." Clearly, if it will do these things we have at our disposal a mighty force, so that in the words of Dr Pilgrim it may be said that " its range of application is almost coextensive with the needs of the ailing physical organism, and is, in varying degree, applicable to almost every form of disease." Such a claim as this is sufficient to make some of us very suspicious, and inclined to tread warily, especially since we are told that the list of diseases in which vibratory treatment has been attended with " results more prompt and satisfactory than by any other recognised methods of treatment," includes the various forms of nervous disorders?neurasthenia, melancholia, insomnia, hysteria, and the like?"in all of which beneficial effects were realised from the first treatments "?a thing quite in accordance with what is often seen in the treatment of such neuroses
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