Dynamics of oligomer populations formed during the aggregation of Alzheimer’s Aβ42 peptide

Investigating the effects of molecular crowding on the kinetics of protein aggregation

“…4, which shows the quantity 1 / versus , which controls the change to the association and nucleation rate constants in Eqs. (17) and (21), clearly shows a ratio 1 ≤ ≈ 0.8 for which crowders essentially do not affect the growth rates (red line) for increasing . Values greater than 0.8 show that the aggregation speeds up with increasing , while the opposite is observed for ratios below 0.8 where aggregation is increasingly slowed down with increasing .…”

“…[5][6][7][8][9] Decades of protein self-assembly studies reveal that the molecular reactions involved are complicated and some new ones are still being discovered, especially in the field of amyloid formation. [10][11][12][13][14][15][16][17] Experimental investigations have shown that both the folding of the constituent monomer proteins as well as the aggregate assembly are determined by a complex energy landscape, where numerous routes can convert monomer proteins into distinct aggregated structures that may or may not have biological functions. 18 Among the many theoretical methods to investigate the protein aggregation problem, the kinetic approaches 10,11,14,[19][20][21][22][23][24][25][26] often provide direct fits to experimental data and interpretation of the aggregation processes.…”

Identification of on- and off-pathway oligomers in amyloid fibril formation

“…We illustrate how this may be done using kinetic data on oligomers produced transiently during bril formation reactions at 37 C for Ab42 (ref. 21) under conditions dominated by secondary nucleation, and for a-synuclein, 25 at conditions where secondary nucleation is absent, 57 and at 22 C for K18 tau, 11 i.e. residues 243-274 of the major isoform tau441, under conditions where aggregation is induced by heparin.…”

“…20 Recent advances in single molecule experimental techniques, as well as isotope-based quantication using radio-assays or mass spectrometry, 9,21 have allowed researchers to record the timedependence of the concentration of oligomeric species present during amyloid bril formation. 8,[21][22][23] This has prompted the development of new theoretical models that leverage the framework of chemical kinetics to determine from such data the mechanisms of oligomer-mediated amyloid bril formation. 10,11,13,21,[24][25][26]64 A fundamental goal of such quantitative studies is to elucidate the precise relationship between oligomers and brils.…”

“…8,[21][22][23] This has prompted the development of new theoretical models that leverage the framework of chemical kinetics to determine from such data the mechanisms of oligomer-mediated amyloid bril formation. 10,11,13,21,[24][25][26]64 A fundamental goal of such quantitative studies is to elucidate the precise relationship between oligomers and brils. Such knowledge would enhance our understanding of the molecular mechanisms underlying Alzheimer's and other protein misfolding diseases, and in so doing could transform current approaches to rational drug design for the treatment of these conditions.…”