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Updated: Jun 27, 2026
Visualization of Amyloid β Deposits in the Human Brain with Matrix-assisted Laser Desorption/Ionization Imaging Mass Spectrometry
Published on: March 7, 2019
apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain
Rashid Deane1, Abhay Sagare, Katie Hamm
1Center for Neurodegenerative and Vascular Brain Disorders, Department of Neurosurgery, University of Rochester Medical School, Rochester, New York 14642, USA.
Abstract:
Neurotoxic amyloid beta peptide (Abeta) accumulates in the brains of individuals with Alzheimer disease (AD). The APOE4 allele is a major risk factor for sporadic AD and has been associated with increased brain parenchymal and vascular amyloid burden. How apoE isoforms influence Abeta accumulation in the brain has, however, remained unclear. Here, we have shown that apoE disrupts Abeta clearance across the mouse blood-brain barrier (BBB) in an isoform-specific manner (specifically, apoE4 had a greater disruptive effect than either apoE3 or apoE2). Abeta binding to apoE4 redirected the rapid clearance of free Abeta40/42 from the LDL receptor-related protein 1 (LRP1) to the VLDL receptor (VLDLR), which internalized apoE4 and Abeta-apoE4 complexes at the BBB more slowly than LRP1. In contrast, apoE2 and apoE3 as well as Abeta-apoE2 and Abeta-apoE3 complexes were cleared at the BBB via both VLDLR and LRP1 at a substantially faster rate than Abeta-apoE4 complexes. Astrocyte-secreted lipo-apoE2, lipo-apoE3, and lipo-apoE4 as well as their complexes with Abeta were cleared at the BBB by mechanisms similar to those of their respective lipid-poor isoforms but at 2- to 3-fold slower rates. Thus, apoE isoforms differentially regulate Abeta clearance from the brain, and this might contribute to the effects of APOE genotype on the disease process in both individuals with AD and animal models of AD.
Insights
Apolipoprotein E (ApoE) isoforms differentially impact amyloid beta (Abeta) clearance from the brain. ApoE4 significantly hinders Abeta removal across the blood-brain barrier, unlike ApoE2 and ApoE3.
Area of Science:
- Neuroscience
- Biochemistry
- Genetics
Background:
- Alzheimer disease (AD) is characterized by neurotoxic amyloid beta (Abeta) peptide accumulation.
- The Apolipoprotein E4 (APOE4) allele is a significant risk factor for AD, linked to increased amyloid burden.
Purpose of the Study:
- To investigate how different apolipoprotein E (ApoE) isoforms influence Abeta accumulation in the brain.
- To elucidate the mechanism by which ApoE isoforms affect Abeta clearance across the blood-brain barrier (BBB).
Main Methods:
- Utilized mouse models to study the clearance of Abeta peptides across the blood-brain barrier (BBB).
- Investigated the role of low-density lipoprotein receptor-related protein 1 (LRP1) and very low-density lipoprotein receptor (VLDLR) in ApoE-mediated Abeta transport.
- Compared the clearance rates of Abeta-ApoE complexes involving different ApoE isoforms (ApoE2, ApoE3, ApoE4).
Main Results:
- ApoE isoforms differentially disrupt Abeta clearance at the BBB; ApoE4 exhibits a greater disruptive effect than ApoE3 or ApoE2.
- Abeta binding to ApoE4 redirects clearance from LRP1 to VLDLR, resulting in slower internalization of Abeta-ApoE4 complexes.
- Abeta-ApoE2 and Abeta-ApoE3 complexes are cleared more rapidly via both VLDLR and LRP1 compared to Abeta-ApoE4 complexes.
Conclusions:
- ApoE isoforms play a critical role in regulating Abeta clearance from the brain via the BBB.
- The differential clearance mechanisms mediated by ApoE isoforms may contribute to the influence of APOE genotype on Alzheimer disease pathogenesis.
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