Roles of ApoE4 on the Pathogenesis in Alzheimer's Disease and the Potential Therapeutic Approaches

Abstract

The Apolipoprotein E ε4 (ApoE ε4) allele, encoding ApoE4, is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). Emerging epidemiological evidence indicated that ApoE4 contributes to AD through influencing β-amyloid (Aβ) deposition and clearance. However, the molecular mechanisms of ApoE4 involved in AD pathogenesis remains unclear. Here, we introduced the structure and functions of ApoE isoforms, and then we reviewed the potential mechanisms of ApoE4 in the AD pathogenesis, including the effect of ApoE4 on Aβ pathology, and tau phosphorylation, oxidative stress; synaptic function, cholesterol transport, and mitochondrial dysfunction; sleep disturbances and cerebrovascular integrity in the AD brains. Furthermore, we discussed the available strategies for AD treatments that target to ApoE4. In general, this review overviews the potential roles of ApoE4 in the AD development and suggests some therapeutic approaches for AD. ApoE4 is genetic risk of AD. ApoE4 is involved in the AD pathogenesis. Aβ deposition, NFT, oxidative stress, abnormal cholesterol, mitochondrial dysfunction and neuroinflammation could be observed in the brains with ApoE4. Targeting the interaction of ApoE4 with the AD pathology is available strategy for AD treatments.

Keywords: Alzheimer’s disease (AD); Apolipoprotein E4 (ApoE4); Therapy; β-Amyloid (Aβ).

Fig. 1

The structure of ApoE isoforms

Fig. 2

Roles of ApoE4 in Aβ pathology. ApoE4 binds to Aβ and form a complex that affects Aβ clearance and accelerates its accumulation and deposition in the brain. ApoE4 makes the ApoE receptor more susceptible to binding to dual leucine-zipper kinase (DLK), activates ERK1/2 MAP kinase and induces cFos phosphorylation, stimulates transcription factor AP-1, resulting in enhanced APP transcription, increased APP expression, and consequently increased Aβ

Fig. 3

Roles of ApoE4 in tau phosphorylation. Astrocytes expressing ApoE4 exacerbate the phosphorylation level of tau protein in neurons, which in turn forms NFT. The astrocytes with ApoE4 can facilitate astrocyte-secreted protein glypican-4 (GPC-4) to neurons to promote tau phosphorylation

Fig. 4

Roles of ApoE4 in synaptic impairment. ApoE4 retains ApoER2 and glutamate receptors in endosomal compartments. Synaptic transmission mediated by reelin is inhibited and ApoE on the surface of neurons is decreased. ApoE4 can contribute to neuronal and synaptic dysfunction by activation of cyclophilin-A matrix metalloproteinase-9 (CypA-MMP9) pathway. ApoE4 would lead to the accumulation of Aβ, inducing synaptic impairment

Fig. 5

Regulation of cholesterol in brain mediated by ApoE4. ApoE4 decreases ABCA1 cycling by promoting increased expression of ADP-ribosylation factor 6 (ARF6), which in turn decreases ABCA1 cycling to the cell membrane in astrocytes and affects cholesterol distribution. astrocytes with ApoE4 accumulate excess cholesterol and increase the level of APP in lipid rafts. Cholesterol clearance depends on its catabolic derivative, 24S-hydroxycholesterol (24-OHC). Elevated 27-OHC can activate C/EBPβ at the presence ApoE4, which subsequently increases Aβ production

Fig. 6

Influence of ApoE4 in mitochondrial dysfunction. When the neurons are stressed, ApoE4 expression in neuron cells would inhibit the generation of ATP, increase the reactive oxygen species (ROS) level and promotes calcium overload. Some proteins about mitochondrial biogenesis and dynamics could be reduced when ApoE4 presents. ApoE4 fragments also lead to mitochondrial dysfunction and endoplasmic reticulum (ER) stress, as well as the formation of mitochondrial-associated membrane (MAM)

Fig. 7

Neuroinflammation effects of ApoE4 in AD pathogenesis. ApoE4 induces the increase of inflammatory factors, including TNF-α and IL-6. ApoE4 could exacerbate neuroinflammation through activating the proinflammatory PGE2 pathway or inhibiting the anti-inflammatory TREM2 pathway. ApoE4 also can contribute to neuroinflammation through inducing Ca²⁺ dependent phospholipase A2 (cPLA2) activations and changes on arachidonic acid (AA) signaling cascades. Further, ApoE4 affects Aβ clearance mediated by the interaction between ApoE4 and TREM2

Fig. 8

AD therapy targeting to ApoE. Targeting ApoE4 is highly promising for AD treatment and improvement. Considering the roles of ApoE4 in the LOAD pathogenesis, the therapeutic approaches can be subdivided into the following categories: targeting the interaction of ApoE with Aβ, targeting ApoE receptors, correcting the ApoE4 genotype by gene editing (CRISPR/Cas9), ApoE antibody, and nonpharmacological therapy