Amyloid deposits are found in numerous neurodegenerative pathologies, including Parkinson's disease and Alzheimer's disease. These deposits are toxic and composed of protein aggregates arranged in amyloid fibrils showing a characteristic oligomeric structure rich in β-sheets.
The pathological aggregation of the Tau protein is involved in around twenty tauopathies, including Alzheimer's disease, the most frequent form of dementia. In healthy cells, the homeostasis of Tau (and other proteins) is finely regulated by a "quality control system" mediated in part by chaperone proteins. This system protects the proteome by regulating not only the synthesis, conformation and cellular trafficking of native proteins, but also the degradation of faulty proteins.
Numerous in vitro and in vivo studies have demonstrated an association between the molecular activity of chaperone proteins and the aggregation of Tau. It is known that chaperone proteins belonging to the Hsp70 family slow fibril formation, but there is little current knowledge as to what conditions chaperone proteins need to disassemble amyloid fibrils, a difficult task due to the thermodynamic stability of these latter.
In an in vitro study published in The Journal of Biological Chemistry, researchers from MIRCen's Neurodegenerative Diseases Laboratory and their partners at Heidelberg University1,2, the Universities of Cambridge3,4 and Groningen and the company AbbVie demonstrated a machinery for the disaggregation of Tau amyloid fibrils involving human Hsp70 chaperone proteins. This machinery was able to disassemble into smaller mono or oligomers the recombinant fibrils of the six known Tau isoforms as well as aggregates obtained from cellular models or patients with Alzheimer's disease. Surprisingly though, in follow-up in vitro experiments, the resulting components presented a potential for propagation and infectivity greater than that of complete fibrils.
The team's results suggest that the chaperone proteins play an essential role in the early stages of disease when the first aggregates form, but also a deleterious role in the more advanced disease stages. Thus, in its doggedness to disassemble the amyloid fibrils, this machinery ends up creating smaller—but just as toxic—Tau species that contribute not to controlling the disease, but making it progress.
With their study, the researchers have brought a better understanding of the regulation of the Hsp70 chaperone family, which may prove useful for targeted therapies in tauopathies, including Alzheimer's disease.
1 : Center for Molecular Biology of Heidelberg University (ZMBH) and German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
2 : Schaller Research Group Proteostasis in Neurodegenerative Disease of Heidelberg University and German Cancer Research Center (DKFZ), Heidelberg, Germany
3 : Department of Clinical Neurosciences, UK Dementia Research Institute at the University of Cambridge, Cambridge, United Kingdom
4 : Department of Neuropathology, Cambridge Universities Hospital Trust, Cambridge, United Kingdom