Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Apolipoprotein E (APOE) is the primary genetic risk factor for late-onset Alzheimer's disease (AD).
• Three APOE isoforms (APOE2, APOE3, APOE4) differentially affect AD risk and tau pathology.
• Knowledge gaps exist regarding tau polymorphism across APOE isoforms.

Purpose of the Study:

• To characterize tau oligomers associated with each APOE isoform.
• To investigate the impact of APOE isoforms on tau oligomer conformation and function.

Main Methods:

• Isolation of brain-derived tau oligomers and fibrils from patients with varying APOE genotypes.
• Proteinase K (PK) digestion and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess tau oligomer stability and PK cleavage sites.
• Electrophysiology to evaluate the synaptotoxicity of tau oligomers.

Main Results:

• Tau oligomers exhibit distinct proteolytic stability and cleavage site profiles across APOE isoforms, indicating conformationally different polymorphs.
• These tau oligomer polymorphs differentially impair synaptic function in an APOE isoform-specific manner.
• APOE4-associated tau oligomers demonstrated the most significant impairment of synaptic functioning.

Conclusions:

• Distinct APOE isoforms correlate with specific tau oligomer polymorphs possessing varying synaptotoxicity.
• Therapeutic strategies for Alzheimer's disease must consider APOE isoform.
• Targeting APOE isoform-specific tau oligomers presents a potential novel therapeutic approach for AD.