APOE isoform-associated tau oligomer polymorphs differ in synaptotoxicity and seeding activity

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Pathological tau aggregates exhibit diverse polymorphic forms in diseases like Alzheimer's disease (AD).
• The influence of apolipoprotein E (APOE) isoforms (ε2, ε3, ε4) on tau aggregate polymorphism and associated pathology remains largely unknown.
• APOE ε4 is a significant genetic predictor of late-onset AD.

Purpose of the Study:

• To investigate tau aggregate polymorphism across different APOE isoforms.
• To assess the conformational and bioactivity differences of tau oligomers influenced by APOE genotypes.
• To determine the impact of APOE-associated tau oligomers on synaptic plasticity and seeding activity.

Main Methods:

• Analysis of tau oligomers from 14 patients with diverse APOE genotypes.
• Assessment of conformational properties through proteolytic stability and cleavage site profiling.
• Evaluation of bioactivity, including effects on synaptic plasticity and tau seeding potential.

Main Results:

• Tau oligomers display distinct conformations and proteolytic profiles dependent on APOE isoform.
• APOE ε4-associated tau oligomers exhibit the highest potency in impairing synaptic plasticity.
• APOE ε4-associated tau oligomers show significantly higher seeding activity compared to other isoforms.
• Synaptotoxicity and seeding activity of tau oligomers are independent characteristics.

Conclusions:

• APOE isoforms are linked to distinct tau oligomer polymorphs with varying bioactivities.
• APOE ε4-associated tau oligomers represent a particularly toxic species, strongly impacting synaptic function.
• Targeting specific tau polymorphs, especially those associated with APOE ε4, offers a promising therapeutic strategy for AD.
• Understanding APOE's role in tau pathology is crucial for developing effective AD treatments.