Chemistry
Differential Effects of Aβ Peptides on the Plasmin-Dependent Degradation of ApoE3 and ApoE4
Document Type
Article
Abstract
The ApoE4 allele of apolipoprotein E (ApoE4) is the strongest hereditary predisposition to Alzheimer’s disease, even though ApoE4 only differs from the more common ApoE3 by a single amino acid substitution. Previous studies have shown that ApoE4 is more susceptible to proteolytic degradation than ApoE3. This is an important finding because of ApoE’s role in cholesterol homeostasis and lipid transport in the brain. The molecular determinants of the increased susceptibility of ApoE4 to proteolysis are unknown. Here, we apply a combination of spectrometric and spectroscopic methods to show that amyloid-β (Aβ) peptides, including Aβ(1-40) and Aβ(pyroE3-42), differentially modulate the plasmin-dependent degradation of ApoE3 and ApoE4. In particular, our data reveal that while the Aβ peptides do not affect the proteolysis of ApoE3, the peptides enhance the degradation of ApoE4 significantly. Overall, this work motivates therapeutic development that targets the Aβ-induced dysregulation of ApoE4 homeostasis in individuals carrying the ApoE4 allele. © 2025 American Chemical Society.
Publication Title
ACS Chemical Neuroscience
Publication Date
2025
ISSN
1948-7193
DOI
10.1021/acschemneuro.5c00065
Keywords
Alzheimer’s disease, amyloid-β, ApoE4 proteolysis, ApoE4 structure, apolipoprotein E, plasmin
Repository Citation
Kemeh, Merc M.; Furnelli, Anthony J.; and Lazo, Noel, "Differential Effects of Aβ Peptides on the Plasmin-Dependent Degradation of ApoE3 and ApoE4" (2025). Chemistry. 49.
https://commons.clarku.edu/chemistry/49
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