ApoE: The Non-Protagonist Actor in Neurological Diseases

Abstract

Background: Apolipoprotein E (APOE = gene, ApoE = protein) is a glycoprotein involved in the biological process of lipid transportation and metabolism, contributing to lipid homeostasis. APOE has been extensively studied for its correlation with neurodegenerative diseases, in particular Alzheimer's disease (AD), where the possession of the epsilon 4 (E4) allele is established as a risk factor for developing AD in non-familiar sporadic forms. Recently, evidence suggests a broad involvement of E4 also in other neurological conditions, where it has been shown to be a predictive marker for worse clinical outcomes in Parkinson's disease (PD), brain trauma, and disturbances of consciousness. The mechanisms underlying these associations are complex and involve amyloid-β (Aβ) peptide accumulation and neuroinflammation, although many others have yet to be identified.

Objectives: The aim of this review is to overview the current knowledge on ApoE as a non-protagonist actor in processes underlying neurodegenerative diseases and its clinical significance in AD, PD, acquired brain trauma, and Disorders of Consciousness (DoC). Ethical implications of genetic testing for APOE variants and information disclosure will also be briefly discussed.

Keywords: Alzheimer’s disease; Parkinson’s disease; apolipoprotein E; brain injury; dementia; neurodegenerative diseases; neuroinflammation; stroke.

Figure 3

Physiological (top) and pathological (bottom) roles of ApoE in neurodegenerative diseases. ApoE regulates the immunomodulatory activity of microglia and blood–brain barrier integrity. In pathological conditions, ApoE4 promotes the accumulation of lipid droplets in the astrocyte cytoplasm, reduces Aβ uptake, leading to Aβ oligomerization, fibrillation, and seeding into Aβ plaques [1,11,12]. ApoE4 seems to induce hyperphosphorylation of Tau, which accumulates in neurons, leading to the formation of neurofibrillary tangles and synaptic dysfunction [54]. This image was created with BioRender.com (https://www.biorender.com/, accessed on 15 September 2024).

Figure 1

Schematic representation of the APOE gene. APOE is activated after the cleavage of the secretion peptide and consists of an N-terminal domain comprising four bundled α-helices and a helical C-terminal domain separated by an unstructured hinge region. The N-terminal domain contains the receptor-binding site (residues 136-150), and the C-terminal domain contains the lipid-binding region (residues 244-272) and a self-association region. This image was created with BioRender.com (https://www.biorender.com/, accessed on 15 September 2024).

Figure 2

(a) 3D model of ApoE3 [24] and ApoE4 [25] α-helix 1 to 4. Superimposed structures of ApoE3 (1BZ4) (blue) and ApoE4 (8AX8) (gray) templates from PDB (RCSB.org) and Uniprot (https://www.uniprot.org/, accessed on 15 September 2024) respectively. The amino acid sequence alignment highlighting C112-R158 polymorphism is also shown. Missense mutations at C112-R158 result in greater exposure of the side chain given the aliphatic nature of the arginine residue. (b) Depiction of protein surface differences between ApoE3 and ApoE4. ApoE may exhibit variant-dependent activity in lipid trafficking and Aβ binding. For instance, during coordination with LDLR for lipidation, surface charge is determinant within in silico models [28]. Molecular graphics and analyses were performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311.