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Alzheimer's disease pathology propagation by exosomes containing toxic amyloid-beta oligomers
Maitrayee Sardar Sinha1, Anna Ansell-Schultz1, Livia Civitelli1
1Department of Pathology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Abstract:
The gradual deterioration of cognitive functions in Alzheimer's disease is paralleled by a hierarchical progression of amyloid-beta and tau brain pathology. Recent findings indicate that toxic oligomers of amyloid-beta may cause propagation of pathology in a prion-like manner, although the underlying mechanisms are incompletely understood. Here we show that small extracellular vesicles, exosomes, from Alzheimer patients' brains contain increased levels of amyloid-beta oligomers and can act as vehicles for the neuron-to-neuron transfer of such toxic species in recipient neurons in culture. Moreover, blocking the formation, secretion or uptake of exosomes was found to reduce both the spread of oligomers and the related toxicity. Taken together, our results imply that exosomes are centrally involved in Alzheimer's disease and that they could serve as targets for development of new diagnostic and therapeutic principles.
Insights
Small extracellular vesicles, known as exosomes, carry toxic amyloid-beta oligomers in Alzheimer's disease brains. Targeting these exosomes may offer new diagnostic and therapeutic strategies for Alzheimer's disease.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Alzheimer's disease (AD) involves progressive cognitive decline linked to amyloid-beta (Aβ) and tau pathology.
- The prion-like spread of Aβ oligomers is implicated in AD pathogenesis, but mechanisms remain unclear.
Purpose of the Study:
- To investigate the role of small extracellular vesicles (exosomes) in the propagation of Aβ pathology in Alzheimer's disease.
- To determine if exosomes from AD patients can mediate neuron-to-neuron transfer of toxic Aβ oligomers.
Main Methods:
- Analysis of exosomes isolated from Alzheimer's disease patient brains.
- In vitro studies using cultured neurons to assess exosome-mediated Aβ oligomer transfer and toxicity.
- Experimental blockade of exosome formation, secretion, and uptake.
Main Results:
- Exosomes from AD brains show elevated levels of amyloid-beta oligomers.
- These exosomes facilitate the transfer of toxic Aβ oligomers to recipient neurons.
- Inhibiting exosome pathways significantly reduced Aβ oligomer spread and associated toxicity.
Conclusions:
- Exosomes play a critical role in the intercellular propagation of Alzheimer's disease pathology.
- Exosomes represent a potential therapeutic target for halting or slowing Alzheimer's disease progression.
- Exosomes may also serve as diagnostic biomarkers for Alzheimer's disease.