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Updated: Oct 26, 2025
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
Endo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting
Marie P Schützmann1, Filip Hasecke1, Sarah Bachmann2
1Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany.
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.
Insights
Alzheimer's disease peptide (Aβ) oligomers form faster in acidic neuron compartments, driving Tau pathology. This suggests endosomes are key sites for toxic Aβ oligomer assembly.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Amyloid-β oligomers (AβOs) are potent drivers of Alzheimer's disease pathology.
- AβOs are more toxic than amyloid fibrils, causing synaptic dysfunction and Tau pathology.
- Aβ accumulates in acidic endo-lysosomal vesicles within neurons.
Purpose of the Study:
- To investigate the effect of pH on AβO assembly rate and mechanism.
- To determine if the endo-lysosomal system facilitates AβO formation in neurons.
- To explore the role of AβOs in Tau missorting and neuronal dysfunction.
Main Methods:
- In vitro kinetic studies of Aβ assembly at varying pH.
- Neuronal cell culture models.
- Biochemical and imaging techniques to detect AβOs, Tau pathology, and synaptic function.
Main Results:
- AβO assembly is accelerated ~8,000-fold at acidic pH, favoring oligomers over fibrils.
- Acidic pH and high Aβ concentration promote extensive Aβ42 oligomer formation in vitro.
- Targeting dimeric Aβ variants (dimAβ) to neurons induced AβO formation, Tau missorting, and impaired neuronal activity.
Conclusions:
- The endosomal/lysosomal system is a critical site for the assembly of pathomechanistically relevant AβOs.
- pH-dependent AβO formation contributes to Alzheimer's disease pathogenesis.
- Targeting AβO assembly within endosomes may offer therapeutic strategies.
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