Age-Dependent Protein Aggregation Initiates Amyloid-β Aggregation.

Area of Science:

• Neuroscience
• Molecular Biology
• Aging Research

Background:

• Aging is the primary risk factor for neurodegenerative diseases, characterized by pathological protein aggregation.
• Widespread protein aggregation occurs during aging, even without disease, but its role in disease initiation is unclear.
• Some age-associated aggregation-prone proteins are found in hallmark disease aggregates, suggesting potential cross-seeding.

Purpose of the Study:

• To investigate whether age-dependent protein aggregation can initiate amyloid-β (Aβ) aggregation.
• To identify the specific age periods and proteins involved in initiating Aβ aggregation.

Main Methods:

• In vitro experiments using insoluble proteins from aged and young *Caenorhabditis elegans* and mouse brains.
• Testing the seeding potential of protein aggregates formed at different adult ages in *C. elegans*.
• Mass spectrometry to identify proteins in age-associated aggregates.

Main Results:

• Highly insoluble proteins from aged, but not young, individuals initiated Aβ aggregation in vitro.
• Protein aggregates from early aging stages did not seed Aβ aggregation; middle-age aggregates did.
• Mass spectrometry identified proteins like 14-3-3, Ubiquitin-like modifier-activating enzyme 1, and Lamin A/C as potential cross-seeders.

Conclusions:

• Age-dependent protein aggregation, particularly from middle age, can initiate pathological protein aggregation, contributing to neurodegeneration.
• Specific proteins accumulating with age may act as seeds for hallmark aggregates like amyloid-β plaques.
• Targeting age-related protein misfolding and aggregation may offer therapeutic strategies for neurodegenerative diseases.