Oligomer-specific Abeta toxicity in cell models is mediated by selective uptake
Sidhartha M Chafekar1, Frank Baas, Wiep Scheper
1Neurogenetics Laboratory Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Biochimica Et Biophysica Acta
|July 8, 2008
Summary
Alzheimer's disease (AD) pathology involves beta-amyloid (Abeta) aggregation. This study shows that only Abeta oligomers, not fibrils, enter cells, explaining their specific toxicity. This finding advances understanding of AD pathogenesis.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) involves beta-amyloid (Abeta) peptide aggregation.
- Misfolded Abeta exists in oligomeric and fibrillar forms, with differing cellular toxicities.
- The differential toxicity is hypothesized to relate to intracellular accessibility.
Purpose of the Study:
- To investigate the cellular uptake mechanisms of Abeta oligomers versus fibrils.
- To determine if selective internalization explains the distinct toxicities of Abeta aggregation states.
Main Methods:
- Utilized fluorescently labeled Abeta1-42 (oligomeric and fibrillar forms).
- Employed cell culture models (HeLa and SKNSH cells).
- Investigated cellular internalization via endocytosis and lysosomal transport; assessed toxicity inhibition.
Main Results:
- Abeta1-42 oligomers were readily internalized by cells, while fibrils were not.
- Oligomer uptake occurred via endocytosis and lysosomal transport.
- Inhibiting oligomer uptake specifically reduced their toxicity, without affecting fibril toxicity.
Conclusions:
- Selective cellular uptake of Abeta oligomers is demonstrated.
- Internalization of Abeta oligomers is a key factor in their specific toxicity in Alzheimer's disease.
- This highlights a critical mechanism differentiating the pathogenic roles of Abeta aggregation states.
