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Updated: May 20, 2025
09:22
In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
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Intraneuronal Aβ accumulation causes tau hyperphosphorylation via endolysosomal leakage
Yang Gao1, Lisha Wang1, Tosca Doeswijk1
1Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Solna, Sweden.
Summary
Alzheimer's disease research reveals amyloid beta (Aβ) triggers tau tangles. Aβ accumulation causes lysosomal leakage, releasing enzymes that promote tau hyperphosphorylation, a key Alzheimer's pathology.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) involves amyloid beta (Aβ) plaques and tau tangles.
- The precise link between Aβ and tau in AD pathogenesis remains unclear.
Purpose of the Study:
- To investigate the mechanism connecting Aβ accumulation to tau hyperphosphorylation.
- To elucidate the role of intraneuronal Aβ42 in downstream tau pathology.
Main Methods:
- Developed a neuronal model for Aβ-induced toxicity.
- Utilized confocal microscopy and live cell imaging to study Aβ42 effects on tau.
- Assessed the impact of lysosomal leakage and enzyme activity.
Main Results:
- Endocytosed Aβ42 accumulated in neurons, forming protofibrils and causing lysosomal leakage.
- Lysosomal leakage released Asparaginyl endopeptidase (AEP), promoting tau hyperphosphorylation.
- Inhibiting AEP activity significantly reduced tau hyperphosphorylation.
Conclusions:
- Aβ42 accumulation in neurons initiates a cascade leading to tau hyperphosphorylation.
- Endolysosomal leakage and subsequent AEP release represent a critical pathway in AD.
- AEP inhibition offers a potential therapeutic strategy for Alzheimer's disease.
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