Elsevier

Biological Psychiatry

Volume 83, Issue 4, 15 February 2018, Pages 347-357
Biological Psychiatry

Review
Apolipoprotein E, Receptors, and Modulation of Alzheimer’s Disease

https://doi.org/10.1016/j.biopsych.2017.03.003Get rights and content

Abstract

Apolipoprotein E (apoE) is a lipid carrier in both the peripheral and the central nervous systems. Lipid-loaded apoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and injury repair in the brain. Considering prevalence and relative risk magnitude, the ε4 allele of the APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE4 contributes to AD pathogenesis by modulating multiple pathways, including but not limited to the metabolism, aggregation, and toxicity of amyloid-β peptide, tauopathy, synaptic plasticity, lipid transport, glucose metabolism, mitochondrial function, vascular integrity, and neuroinflammation. Emerging knowledge on apoE-related pathways in the pathophysiology of AD presents new opportunities for AD therapy. We describe the biochemical and biological features of apoE and apoE receptors in the central nervous system. We also discuss the evidence and mechanisms addressing differential effects of apoE isoforms and the role of apoE receptors in AD pathogenesis, with a particular emphasis on the clinical and preclinical studies related to amyloid-β pathology. Finally, we summarize the current strategies of AD therapy targeting apoE, and postulate that effective strategies require an apoE isoform–specific approach.

Section snippets

Biochemical Features of ApoE

ApoE is a glycoprotein of 299 amino acids with a molecular mass of ∼34 kDa. It transports and delivers cholesterol and other lipids in the plasma and the central nervous system (CNS) via binding to cell surface apoE receptors (Figure 1) 9, 10. The receptor-binding domain of apoE is in the N-terminal domain (residues 136–150), whereas the major lipid-binding region (residues 244–272) resides in the C-terminal domain 6, 8. The three isoforms (apoE2, apoE3, and apoE4) differ at positions 112 and

ApoE Receptors

The low-density lipoprotein receptor (LDLR) family, including LDLR, LDLR-related protein 1 (LRP1), VLDL receptor (VLDLR), and apoE receptor 2 (apoER2), are the major apoE receptors that exhibit distinct binding affinity to apoE with different isoforms and lipidation status (6). LRP1 preferentially binds to recombinant apoE or apoE aggregates, whereas LDLR and VLDLR bind to lipidated apoE particles or lipid-free apoE, respectively 6, 7, 27. In addition to the LDLR family, both lipidated and

Effects of ApoE on Brain Aβ Deposition

Using 18F-florbetapir–positron emission tomography or 11C-Pittsburgh compound B–positron emission tomography imaging, clinical studies showed that cerebral Aβ deposition is positively associated with the APOE4 genotype in cognitively normal subjects, mild cognitive impairment cases, and symptomatic AD patients 32, 33, 34. In addition, amyloid imaging positivity appears to begin earlier in cognitively intact APOE4 carriers (near 56 years of age) than APOE4 noncarriers (at 76 years of age) (35).

Mechanisms of ApoE and ApoE Receptors in Modulating Aβ Metabolism

The Aβ level in the brain represents the net balance of Aβ production and clearance (2); therefore, Aβ accumulation in AD brains may reflect overproduction, inefficient clearance, or both. Mounting evidence demonstrates that apoE and apoE receptors play important roles in these processes, which will be discussed in more detail below (Figure 2).

ApoE and ApoE Receptors in Modulating Synaptic Integrity and Plasticity

Synaptic failure, including synaptic dysfunction and synapse loss, is an early pathological feature of AD 91, 92, 93. It was reported that apoE receptors may be involved in modulating synaptic plasticity. ApoER2 and LRP1 are reported to interact with N-methyl-D-aspartate receptor subunits (94), modulate the internalization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and regulate synaptic plasticity (95). LRP6 and related Wnt signaling are important for

ApoE in Tauopathy, Lipid Transport, Glucose Metabolism, Vascular Function, and Neuroinflammation

Information regarding apoE in tauopathy, lipid transport, glucose metabolism, vascular function, and neuroinflammation can be found in the Supplement.

ApoE Determines Therapeutic Responses

Several clinical trials in AD therapies demonstrated APOE genotype–dependent responses. For example, recent trials revealed that the beneficial effects of intranasal insulin treatment on cognition are modulated by APOE genotype status in AD patients 3, 79, 100. Acute treatment of short-acting intranasal insulin leads to cognitive improvement in AD patients who are APOE4 noncarriers, but not in APOE4 carriers (78). Long-acting intranasal insulin improves cognition in APOE4 AD patients but

Acknowledgments and Disclosures

This work was supported by National Institutes of Health Grant Nos. R01AG046205, R01AG035355, R01AG027924, RF1AG051504, P01NS074969, and P50AG016574 (to GB), a Cure Alzheimer’s Fund Grant (to GB), a fellowship from the BrightFocus Foundation (to C-CL), and a Pilot Grant from Mayo Clinic Alzheimer’s Disease Research Center (to NZ).

We thank Lindsey Felton for her careful reading of the manuscript.

The authors report no biomedical financial interests or potential conflicts of interest.

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