Amyloid-β peptide (Aβ) forms metastable oligomers >50 kDa, termed AβOs, that are more effective than Aβ amyloid fibrils at triggering Alzheimer’s disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, Aβ accumulates in endo-lysosomal vesicles at low pH. Here, we show that the rate of AβO assembly is accelerated 8,000-fold upon pH reduction from extracellular to endo-lysosomal pH, at the expense of amyloid fibril formation. The pH-induced promotion of AβO formation and the high endo-lysosomal Aβ concentration together enable extensive AβO formation of Aβ42 under physiological conditions. Exploiting the enhanced AβO formation of the dimeric Aβ variant dimAβ we furthermore demonstrate targeting of AβOs to dendritic spines, potent induction of Tau missorting, a key factor in tauopathies, and impaired neuronal activity. The results suggest that the endosomal/lysosomal system is a major site for the assembly of pathomechanistically relevant AβOs.
Many proteins have the potential to aggregate into amyloid fibrils, protein polymers associated with a wide range of human disorders such as Alzheimer's and Parkinson's disease. The thermodynamic stability of amyloid fibrils, in contrast to that of folded proteins, is not well understood: the balance between entropic and enthalpic terms, including the chain entropy and the hydrophobic effect, are poorly characterised. Using a combination of theory, in vitro experiments, simulations of a coarse-grained protein model and meta-data analysis, we delineate the enthalpic and entropic contributions that dominate amyloid fibril elongation. Our prediction of a characteristic temperature-dependent enthalpic signature is confirmed by the performed calorimetric experiments and a meta-analysis over published data. From these results we are able to define the necessary conditions to observe cold denaturation of amyloid fibrils. Overall, we show that amyloid fibril elongation is associated with a negative heat capacity, the magnitude of which correlates closely with the hydrophobic surface area that is buried upon fibril formation, highlighting the importance of hydrophobicity for fibril stability.
Amyloid-β peptide (Aβ) forms metastable oligomers >50 kD, termed AβOs or protofibrils, that are more effective than Aβ amyloid fibrils at triggering Alzheimer's disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, Aβ accumulates in endo-lysosomal vesicles at low pH. Here, we show that the rate of AβO assembly is accelerated 8,000-fold upon pH reduction from extracellular to endolysosomal pH, at the expense of amyloid fibril formation. The pH-induced promotion of AβO formation and the high endo-lysosomal Aβ concentration together enable extensive AβO formation of Aβ42 under physiological conditions. Exploiting the enhanced AβO formation of the dimeric Aβ variant dimAβ we furthermore demonstrate targeting of AβOs to dendritic spines, potent induction of Tau missorting, a key factor in tauopathies, and impaired neuronal activity. The results suggest that the endosomal/lysosomal system is a major site for the assembly of pathomechanistically relevant AβOs. IntroductionAβ amyloid fibrils are highly stable protein aggregates of regular cross-β structure that constitute the main component of the senile plaques in the brains of Alzheimer's disease (AD) patients 1-3 . Although amyloid fibrils can exert toxic activities, metastable Aβ oligomers are thought to represent the main toxic species in AD 3-5 . At sufficiently high monomer concentration, Aβ readily forms oligomers with molecular weights >50 kD with spherical, curvilinear, and annular shapes, where the elongated structures appear as "beads-on-a-string"like assemblies of spherical oligomers 4-11 . While multiple names have been given to these metastable Aβ oligomers, including AβOs, ADDLs, and protofibrils, they seem to be closely related with regard to their structures and detrimental activities, and likely form along a common pathway 6,7,12 . Importantly, this pathway is distinct from that of amyloid fibril formation, i.e., AβOs are not intermediates on the pathway to amyloid fibrils (they are "off-pathway") but constitute an alternative Aβ assembly type with distinct toxic activities ( Fig. 1a) 4,5,11,13 . The distinct nature of Aβ amyloid fibrils and AβOs is also reflected in their different formation kinetics. Aβ amyloid fibrils form by nucleated polymerization with crucial contributions from secondary nucleation processes, resulting in the characteristic sigmoidal growth time courses that feature an extended lag-time 14 . AβOs, on the other hand, form in a lag-free oligomerization reaction that has a substantially higher monomer concentration dependence than amyloid fibril formation 11 .Several lines of evidence support a critical role of AβOs in AD pathogenesis. AβOs of sizes >50 kD are the main soluble Aβ species in biological samples 15 . They are synaptotoxic, disrupt long-term potentiation, and cause cognitive impairment in mouse and non-human primate models 4,8,[16][17][18][19][20][21][22] . Furthermore, AβOs induce oxidative stress, endoplasmic reticulum stress, neuroinflammation, and eli...
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