Abstract
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.
Highlights
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
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]
The assembly kinetics of dimAβ at neutral pH monitored by ThT show a biphasic behavior above a concentration (COC) of ~1.5 μM, with the first phase corresponding to the lag-free oligomerization into AβOs and the second phase reflecting amyloid fibril formation[11] (Fig. 1b, c)
Summary
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. 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]. 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]. AβOs induce missorting of Tau into the somatodendritic compartment as well as Tau hyperphosphorylation, leading to microtubule destabilization and spine loss[23,37,38,39]
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