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Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy

Nature Reviews Neuroscience volume 10, pages 333–344 (2009)Cite this article

Key Points

  • Apolipoprotein E4 (APOE4) is the strongest risk factor for sporadic late-onset Alzheimer's disease (AD), which accounts for the vast majority of AD cases.

  • APOE4 differs from APOE2 and APOE3 at amino acid positions 112 and 158 and has a unique conformation that influences its lipid- and receptor-binding properties.

  • The cellular functions of APOE are mediated by APOE receptors, which are members of the low-density lipoprotein receptor (LDLR) family. LDLR-related protein 1 (LRP1) and the LDLRs are the two major types of APOE metabolic receptors in the brain.

  • APOE receptors regulate amyloid precursor protein (APP) trafficking and processing to amyloid-β (Aβ). Some of these functions are further modified by particular APOE isoforms.

  • APOE and APOE receptors have important roles in Aβ clearance both in the brain parenchyma and in the brain vasculature. APOE3 binds to Aβ more strongly than APOE4, and therefore it is more efficient at mediating Aβ clearance through APOE receptors.

  • APOE fragments generated from APOE4 influence tau phosphorylation and mitochondrial function. However, the mechanisms of these events are poorly understood.

  • The primary function of APOE is to transport lipids from astrocytes to neurons, an event that is crucial for synaptogenesis, synaptic repair, dendritic spine integrity and synaptic functions. APOE4 functions less efficiently than APOE3 in these processes.

  • APOE and APOE receptors are new targets for AD therapy. Several strategies have been reported or proposed.

Abstract

The vast majority of Alzheimer's disease (AD) cases are late-onset and their development is probably influenced by both genetic and environmental risk factors. A strong genetic risk factor for late-onset AD is the presence of the ɛ4 allele of the apolipoprotein E (APOE) gene, which encodes a protein with crucial roles in cholesterol metabolism. There is mounting evidence that APOE4 contributes to AD pathogenesis by modulating the metabolism and aggregation of amyloid-β peptide and by directly regulating brain lipid metabolism and synaptic functions through APOE receptors. Emerging knowledge of the contribution of APOE to the pathophysiology of AD presents new opportunities for AD therapy.

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Figure 1: Schematic representation of human APOE.
Figure 2: Apolipoprotein E receptors, members of the LDLR family.
Figure 3: APP processing pathways regulated by low-density lipoprotein receptor family members and APOE.
Figure 4: Major Aβ clearance pathways in the brain: role of APOE isoforms.
Figure 5: Synapse formation and repair depend on cholesterol transport from astrocytes to neurons by the APOE–APOE receptor pathway.
Figure 6: Roles of APOE isoforms in the healthy brain and AD pathogenesis.

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Acknowledgements

The author wishes to thank P. Tarr, D. Owyoung and members of the Bu laboratory for critical reading and comments on this Review. He apologizes to those whose work is not cited owing to either space limitations or the specific focus of the Review. Work in the author's laboratory is supported by the US National Institutes of Health (grants R01AG027924 and R01AG031784) and a Zenith Fellows Award from the Alzheimer's Association.

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  1. Department of Pediatrics and Department of Cell Biology and Physiology, Hope Center for Neurological Disorders, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, 63110, Missouri, USA

    Guojun Bu

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Ligands and functions of LDLR family members (PDF 170 kb)

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Glossary

Polymorphic allele

A natural variant in a gene that occurs with fairly high frequency (> 1%) in the general population.

Cerebral amyloid angiopathy

(CAA). A neurological condition in which amyloid protein is deposited onto the walls of the arteries of the brain. CAA increases the risk of bleeding into the brain, which causes haemorrhagic stroke.

Molten globule

A partially folded protein state that is found in mildly denaturing conditions, such as low pH, the presence of a mild denaturant or high temperature. It is also used to refer to certain protein folding intermediates.

PDAPP amyloid mouse model

A mouse model of AD in which a human APP transgene bearing the amyloidogenic V717F mutation is overexpressed under the control of the human platelet-derived growth factor-β chain gene promoter.

Endopeptidase

An enzyme that catalyses the hydrolysis of peptide bonds in the interior of a polypeptide chain or protein molecule.

PDGF-APPSw,Ind amyloid mouse model

A mouse model of AD in which a human APP transgene bearing the amyloidogenic V717F, K670N and M671L mutations is overexpressed under the control of the human platelet-derived growth factor-β chain gene promoter.

Tg2576 amyloid mouse model

A mouse model of AD in which a human APP transgene bearing the amyloidogenic K670N and M671L mutations is overexpressed under the control of the hamster prion protein gene promoter.

Protein prenylation and isoprenylation

The covalent attachment of hydrophobic prenyl or isoprenyl groups to a protein. These processes have roles in protein attachment to cell membranes and protein–protein interactions.

ApoE4 targeted replacement (TR) mouse

A model of human APOE4 expression in which the human APOEε4 gene is inserted into the mouse Apoe gene locus. The expression of human APOE4 in these mice temporally and spatially resembles that of endogenous mouse APOE.

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Bu, G. Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10, 333–344 (2009). https://doi.org/10.1038/nrn2620

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