Half a century of amyloids: past, present and future
Publications | July 10, 2020

A dream team of authors including CBNS Senior Researcher Dr Pu-Chun Ke commemorate the half-century of amyloid science in humans by documenting the major milestones in amyloid research to date, from the perspectives of structural biology, biophysics, medicine, microbiology, engineering and nanotechnology.

Amyloid diseases are global epidemics with profound health, social and economic implications and yet remain without a cure. This dire situation calls for research into the origin and pathological manifestations of amyloidosis to stimulate continued development of new therapeutics. In basic science and engineering, the cross-β architecture has been a constant thread underlying the structural characteristics of pathological and functional amyloids and realising that amyloid structures can be both pathological and functional in nature has fuelled innovations in artificial amyloids, whose use today ranges from water purification to 3D printing.

This paper, published in Chemical Society Reviews will be one to cite!

Summary and future work

Much progress has been made in the field of amyloid science. The atomic structures of extensively studied amyloid peptides/proteins has been resolved with improved in vitro fibril preparation and breakthroughs in cryo-TEM and ssNMR technologies. Such progress, however, is contrasted by the lack of success in anti-amyloidosis clinical trials and highlights this persistent question: just how much amyloidosis contributes to cell degeneration in amyloid diseases, alongside ageing, deficiencies in microglial activation and peripheral clearance, as well as other environmental and familial factors? The structural characteristics of amyloid fibrils are essential for clinical classification and, hence, the treatment of amyloid diseases. Indeed, while distinct prion strains are associated with different clinical and pathological phenotypes, variations in AD phenotype correlate with variations in Aβ fibril structure. For example, among AD clinical subtypes, the rapidly progressive form possesses rich polymorphism of Aβ40 fibrils, while the posterior cortical atrophy variant and typical prolonged-duration form shows dominance of a specific Aβ40 fibril structure from seeded growth of AD brain cortex extracts. On the other hand, all three subtypes displayed structural heterogeneity for Aβ42 fibrils. Clearly, amyloid structure offers a basis for deciphering the often nuanced clinical manifestations of amyloid diseases.

Amyloidosis occurs across different organs and biological barriers in vivo, as exemplified by systemic ATTR, AL and AA amyloidoses. On the other hand, amyloid proteins such as Aβ, αS and hIAPP have been detected in systemic circulation, fuelling the hypotheses of cross-seeding, inflammation, the gut microbiota and metabolite amyloid as causative to amyloid diseases. Furthermore, Aβ oligomers have shown a negative effect on constricting human capillaries in AD via signalling to pericytes. Accordingly, the structure and toxicity profiles of amyloid proteins may be examined across different compartments, physiological conditions and pathologies.

Much remains to be understood concerning the structure–function–pathogenesis relationship of amyloid proteins and their structural derivatives, as well as the co-aggregation and cross-seeding of amyloid proteins with environmental proteins. A large body of experimental evidence, particularly from genetics, indicates that the proteins associated with amyloidosis are the central player in pathogeneses. The toxicities of the oligomers and protofibrils are indisputable facts of amyloid proteins. Amyloid plaques are a major culprit for a wide range of debilitating human diseases which remain to be deciphered and, hopefully, eradicated in the coming decades.

Amyloids in current science and technology have evolved significantly beyond their original strictly pathological roles, taking up a novel original profile and illuminating new opportunities which were unthinkable only two decades ago. Two new classes of amyloids have emerged, the functional amyloids and the artificial amyloids, performing challenging and remarkably important roles in vivo as well as in modern nanotechnologies. The unique structural and physicochemical properties shared by pathological, functional and artificial amyloids, have evolved from the debilitating role of the former class in neurodegenerative diseases, to the beneficial tasks played by the two latter classes of amyloids, with a demonstrated and emerging role in modern technologies, and entailing a wealth of applications in environmental remediation, health, composite nanomaterials, energy devices, biosensors, soft matter and 3D printing.

Chemical Society Reviews: Half a century of amyloids: past, present and future.