Endo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting

Amyloid-beta peptide (A beta) forms metastable oligomers >50 kDa, termed A beta Os, that are more effective than A beta amyloid fibrils at triggering Alzheimer's disease-related processes such as synaptic dysfunction and Tau pathology, including Tau mislocalization. In neurons, A beta accumulates in endo-lysosomal vesicles at low pH. Here, we show that the rate of A beta O 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 A beta O formation and the high endo-lysosomal A beta concentration together enable extensive A beta O formation of A beta 42 under physiological conditions. Exploiting the enhanced A beta O formation of the dimeric A beta variant dimA beta we furthermore demonstrate targeting of A beta Os 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 A beta Os. A beta oligomers (A beta O) are thought to represent the main toxic species in Alzheimer's disease but very high A beta concentrations are required to study them in vitro and it remains unknown what role these off-pathway oligomers play in vivo. Here, the authors use a dimeric variant of A beta termed dimA beta, where two A beta 40 units are linked, which facilitates to study A beta O formation kinetics and they observe that A beta off-pathway oligomer formation is strongly accelerated at endo-lysosomal pH, while amyloid fibril formation is delayed. Furthermore, the authors demonstrate that dimA beta is a disease-relevant model construct for pathogenic A beta O formation by showing that dimA beta A beta Os target dendritic spines and induce AD-like somatodendritic Tau missorting.

Automated summary

The formation of A beta oligomers (A beta Os) is significantly accelerated in endo-lysosomal pH conditions, leading to extensive A beta O formation under physiological conditions, which triggers Alzheimer's disease-related pathologies. Exploiting a dimeric variant of A beta, the authors demonstrate that this model construct is relevant for studying pathogenic A beta O formation and its effects on Tau missorting and impaired neuronal activity.