Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Neurodegenerative diseases often feature co-occurring protein aggregates, suggesting molecular cross-links.
• While interactions between Amyloid β (Aβ), hyperphosphorylated Tau (pTau), and alpha-synuclein (αSyn) are known, direct links in aggregate formation are unclear.
• Understanding the mechanistic coupling and pathogenicity of these protein interactions is crucial.

Purpose of the Study:

• To investigate the direct links between the formation of Aβ, pTau, and αSyn aggregates.
• To explore the sequential appearance and cross-induction of these toxic protein aggregates in neurodegeneration.
• To elucidate the role of oxidative stress and lysosomal dysfunction in this process.

Main Methods:

• Primary neuronal cultures (hippocampal and dopaminergic) were treated with Aβ oligomers or αSyn pre-formed fibrils (PFFs).
• Mitochondrial and lysosomal stress, alongside protein accumulation, were assessed.
• Aged mice received stereotaxic injections of Aβ or αSyn PFFs, with subsequent analysis of protein aggregation in various brain regions.

Main Results:

• A strong correlation was observed between toxic αSyn aggregates and pTau accumulation.
• Aggregated αSyn was detected following Aβ injections in the hippocampus.
• The appearance of these toxic aggregates was consistently preceded by significant oxidative stress and lysosomal defects.

Conclusions:

• These findings highlight the complex interplay between Aβ, pTau, and αSyn in neurodegeneration.
• The study demonstrates that these proteins can physically interact and, importantly, induce the formation of each other.
• This cross-induction contributes to neuronal death, underscoring a critical pathogenic mechanism.