Protein misfolding and formation of cross-β structured amyloid fibrils are linked to many neurodegenerative disorders but are also the building blocks of novel biomaterials. Our research aims to understand the underlying mechanisms of amyloid formation to both find treatment strategies against dementia diseases, in particular Alzheimer’s and Parkinson’s disease, and to develop new protein-based materials.
Mechanisms of amyloid-β aggregation and inhibition – the basis for development of Alzheimer’s disease treatments
The Bri2 BRICHOS protein – a key to treat Alzheimer’s disease?
Finding ways to inhibit amyloid-associated toxicity is key to develop efficient therapeutics against amyloid diseases, where molecular chaperones are promising candidates. The chaperone domain BRICHOS is such an example that has been shown to specifically target and decrease toxicity associated with amyloid generation. BRICHOS from Bri2 is expressed in the brain and passes the blood-brain-barrier, and could hence be implemented in AD treatments. Our group found that Bri2 BRICHOS exhibits different assembly states, which appear to execute most efficiently one distinct protective function. Oligomers inhibit non-fibrillar aggregation (i.e. classical molecular chaperone activity), dimers retard amyloid-β 42 (Aβ42) fibrillization and the monomers suppress Aβ42-associated neurotoxicity. Subsequently, we designed a Bri2 BRICHOS single point mutant that stabilizes the monomeric state. It selectively blocks secondary nucleation during Aβ42 aggregation and exhibits a significantly increased capacity to prevent Aβ42 toxicity to hippocampal network activity.
Effect of metal ions and other aggregation modulators on amyloid-β self-assembly
Metal ions are suggested to play a crucial role as aggregation modulators of Aβ aggregation, which is implicated in Alzheimer’s disease. Our group reported that both monovalent silver and divalent zinc ions efficiently inhibit Aβ aggregation by retarding fibril elongation. Further, these metal ions bind monomeric Aβ, and form dynamic metal-ion bound complexes. Our studies also comprises other aggregation modulators to obtain detailed insights into the self-assembly mechanisms to provide the basis for drug development.
Molecular structure and neurotoxicity of in vitro- and in vivo-derived amyloid-β and α-synuclein fibrils
Our research also concerns investigations of Aβ and α-synuclein (αSyn) fibril structures in vitro and derived from AD and PD mouse models, since knowledge about molecular fibril structures and translation to the in vivo situation are the basis for design of novel amyloid inhibitors. In particular interactions with molecular chaperones are in our current research focus, where we apply high-resolution structural techniques such as electron microscopy and solid-state nuclear magnetic resonance.
Development of novel protein production protocols enabled by a customized spider silk domain
Another line of research is the development of facile systems for recombinant production amyloidogenic proteins and peptides. For Aβ, we have recently reported a protocol, which gives exceptionally high yields for monomers of different human Aβ variants based on a designed spider silk domain. This protocol facilitates production of aggregation-prone proteins, also in minimal medium, providing efficient and low-cost production of isotope-labeled proteins and peptides.
Development of novel protein-based biomaterials
Besides their association with diseases, amyloidogenic proteins are widely used in nature as building blocks of functional materials, which exhibit several outstanding properties. Our research aims to design and create new biomaterials based on spider silk proteins in combination with amyloidogenic proteins. In particular, the development of strong and specific metal ion-binding biomaterials is one research focus in our laboratory. Further, we develop methods to functionalize amyloid-based fibrils using the BRICHOS domain.
Work opportunities for Bachelor/Master, PhD and Post-doc students
If you are looking for a Bachelor & Master, PhD and Post-doc project and have the relevant background and interest in our research, please feel free to contact us for potential projects and vacancies.
We are currently announcing a PhD position – please see Jobs at KI.
We acknowledge support for our research from Swedish Society for Medical Research (SSMF), FORMAS, Hedlund Foundation, Alzheimerfonden, Åhlen Foundation, Åke Widberg Foundation, Foundation for Geriatric Diseases, Loo and Hans Osterman, Magnus Bergvall, Gamla Tjänarinnor, Stohnes, Ahrèn, KI Research Foundation Grants, INSTRUCT and iNext-Discovery.
Metal ion coordination delays amyloid-β peptide self-assembly by forming an aggregation-inert complex.
Wallin C, Jarvet J, Biverstål H, Wärmländer S, Danielsson J, Gräslund A, Abelein A
J Biol Chem 2020 05;295(21):7224-7234
High-yield Production of Amyloid-β Peptide Enabled by a Customized Spider Silk Domain.
Abelein A, Chen G, Kitoka K, Aleksis R, Oleskovs F, Sarr M, Landreh M, Pahnke J, Nordling K, Kronqvist N, Jaudzems K, Rising A, Johansson J, Biverstål H
Sci Rep 2020 01;10(1):235
Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state.
Chen G, Abelein A, Nilsson HE, Leppert A, Andrade-Talavera Y, Tambaro S, Hemmingsson L, Roshan F, Landreh M, Biverstål H, Koeck PJB, Presto J, Hebert H, Fisahn A, Johansson J
Nat Commun 2017 12;8(1):2081
Ionic Strength Modulation of the Free Energy Landscape of Aβ40 Peptide Fibril Formation.
Abelein A, Jarvet J, Barth A, Gräslund A, Danielsson J
J Am Chem Soc 2016 06;138(21):6893-902
Zinc as chaperone-mimicking agent for retardation of amyloid β peptide fibril formation.
Abelein A, Gräslund A, Danielsson J
Proc Natl Acad Sci U S A 2015 Apr;112(17):5407-12