Apolipoprotein E Interferes with IAPP Aggregation and Protects Pericytes from IAPP-Induced Toxicity

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Apolipoprotein E (ApoE) is linked to Alzheimer's disease (AD), with the ApoE4 variant as the highest genetic risk factor.
• ApoE interacts with amyloid-β (Aβ) in AD, but its interaction with other amyloid-forming proteins is less understood.
• Islet amyloid polypeptide (IAPP) forms amyloid fibrils implicated in type-2 diabetes and potentially AD pathology and vascular dementia.

Purpose of the Study:

• To investigate the impact of ApoE on IAPP aggregation.
• To assess ApoE's effect on IAPP-induced toxicity in blood vessel pericytes.
• To compare the protective potential of different ApoE variants against IAPP toxicity.

Main Methods:

• In vitro assays to study IAPP amyloid formation in the presence of ApoE.
• Cell-based assays using blood vessel pericytes to evaluate IAPP-induced toxicity.
• Analysis of ApoE's interference with IAPP nucleation and elongation phases of aggregation.

Main Results:

• ApoE significantly inhibits IAPP amyloid formation even at substoichiometric concentrations.
• ApoE interferes with both the nucleation and elongation steps of IAPP aggregation.
• ApoE protects pericytes from IAPP-induced toxicity, with ApoE4 exhibiting the weakest protective effect.

Conclusions:

• ApoE possesses a general ability to interfere with amyloid formation and cytotoxicity.
• The ApoE4 variant demonstrates a loss of function in inhibiting IAPP aggregation and toxicity.
• These findings highlight ApoE's broader role in amyloid-related pathologies beyond Alzheimer's disease.