Transglutaminases Derived from Astrocytes Accelerate Amyloid β Aggregation

Area of Science:

• Neuroscience
• Biochemistry
• Cell Biology

Background:

• Astrocytes are activated in neurodegenerative diseases like Alzheimer's disease (AD).
• Transglutaminases (TGs), particularly TG2, are implicated in AD pathology and process amyloid-beta (Aβ), a key aggregate in AD.
• The specific role of astrocyte-derived TGs in Aβ aggregation is not fully understood.

Purpose of the Study:

• To investigate the influence of cultured astrocytes on amyloid-beta (Aβ) aggregation.
• To determine the role of transglutaminases (TGs) in astrocyte-mediated Aβ aggregation.
• To explore the potential feedback loop between aggregated Aβ and TG2 expression in astrocytes.

Main Methods:

• Cultured rat embryonic astrocytes were used to study Aβ aggregation.
• Amyloid-beta (Aβ) monomers were incubated with astrocytes and astrocyte-conditioned medium.
• Transglutaminase (TG) activity was inhibited using cystamine.
• TG2 expression in astrocytes was measured after stimulation with aggregated Aβ.

Main Results:

• Astrocytes reduced Aβ monomer levels but did not significantly alter Aβ oligomer levels when directly incubated with freshly prepared Aβ.
• Aβ oligomer formation increased over time in astrocyte-conditioned medium, an effect inhibited by cystamine.
• Stimulation of astrocytes with aggregated Aβ led to a significant increase in TG2 expression.

Conclusions:

• Astrocytes may internalize Aβ monomers, potentially aiding clearance.
• Astrocyte-derived TGs appear to promote Aβ aggregation.
• Aggregated Aβ may induce TG2 expression in astrocytes, creating a detrimental cycle in Alzheimer's disease.
• Modulating TG activity and expression in astrocytes could be a therapeutic strategy for AD.