Amyloid β-Derived Diffusible Ligands (ADDLs) Induce Abnormal Autophagy Associated with Aβ Aggregation Degree

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Autophagy dysfunction is implicated in Alzheimer's disease (AD) pathogenesis.
• Amyloid β-derived diffusible ligands (ADDLs) are toxic oligomers of amyloid β (Aβ) implicated in AD.
• The role of ADDLs in autophagy-related AD pathogenesis requires further investigation.

Purpose of the Study:

• To investigate the involvement of specific ADDL subsets in autophagy.
• To determine the correlation between ADDL aggregation and autophagy pathway modulation.
• To explore the impact of ADDLs on the MTOR pathway in AD pathogenesis.

Main Methods:

• Generation and characterization of ADDL subsets (A-0, A-12, A-24, A-48) based on assembly time.
• Secondary structure analysis of ADDLs using circular dichroism (CD) spectroscopy.
• In vitro exposure of neuronal and non-neuronal cells to ADDLs, followed by detection of autophagic markers via Western blot and LC3 puncta analysis.

Main Results:

• Exposure to ADDLs induced LC3 puncta (autophagosomes), with the strongest induction observed with the A-24 subset.
• CD spectroscopy revealed decreased α-helix and increased β-strand/β-turn content during ADDL assembly (0-24 h).
• Western blot analysis showed increased LC3B-II/I ratio and decreased SQSTM1/p62 levels, indicating enhanced autophagy.
• A-24 exposure led to a significant decrease in phosphorylated p70 S6 kinase (p-p70 S6 kinase) levels, suggesting MTOR pathway inhibition.

Conclusions:

• ADDL-induced abnormal autophagy is linked to the degree of Aβ aggregation.
• The MTOR pathway is modulated by ADDLs, potentially contributing to AD pathogenesis.
• Specific ADDL subsets and their aggregation state play a role in disrupting autophagy homeostasis in Alzheimer's disease.