ApoE in Alzheimer's disease: pathophysiology and therapeutic strategies

Ana-Caroline Raulin, Sydney V Doss, Zachary A Trottier, Tadafumi C Ikezu, Guojun Bu, Chia-Chen Liu, Ana-Caroline Raulin, Sydney V Doss, Zachary A Trottier, Tadafumi C Ikezu, Guojun Bu, Chia-Chen Liu

Abstract

Alzheimer's disease (AD) is the most common cause of dementia worldwide, and its prevalence is rapidly increasing due to extended lifespans. Among the increasing number of genetic risk factors identified, the apolipoprotein E (APOE) gene remains the strongest and most prevalent, impacting more than half of all AD cases. While the ε4 allele of the APOE gene significantly increases AD risk, the ε2 allele is protective relative to the common ε3 allele. These gene alleles encode three apoE protein isoforms that differ at two amino acid positions. The primary physiological function of apoE is to mediate lipid transport in the brain and periphery; however, additional functions of apoE in diverse biological functions have been recognized. Pathogenically, apoE seeds amyloid-β (Aβ) plaques in the brain with apoE4 driving earlier and more abundant amyloids. ApoE isoforms also have differential effects on multiple Aβ-related or Aβ-independent pathways. The complexity of apoE biology and pathobiology presents challenges to designing effective apoE-targeted therapeutic strategies. This review examines the key pathobiological pathways of apoE and related targeting strategies with a specific focus on the latest technological advances and tools.

Conflict of interest statement

GB consults for SciNeuro and Lexeo, has consulted for AbbVie, E-Scape, Eisai, and Vida Ventures, and is on the scientific advisory board for Kisbee Therapeutics. All other authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Structural model of apoE highlighting AD-related amino acid variations. ApoE is a 299 amino acid glycoprotein with a molecular weight of 34 kDa (PDB 2L7B). It is formed of two independently folded domains linked by a hinge region: the N-terminal domain (residues 1-167) contains the receptor-binding region while the C-terminal domain (residues 206–299) includes the lipid-binding region. There are three major apoE isoforms that differ at amino acid positions 112 and 158: apoE2 (C112/C158); apoE3 (C112/R158); and apoE4 (R112/R158). Additional rare apoE variants have been identified: apoE3-Christchurch (R136S), apoE3-Jacksonville (apoE3-V236E), and apoE4-R251G
Fig. 2
Fig. 2
ApoE-targeted therapeutic strategies for AD. One avenue of AD therapy is modulating apoE expression from various cell types. This can be achieved through LXR/RXR agonists which increase apoE levels and lipidation. LXR/RXRs are upstream regulators of apoE expression making them a suitable target for modulating apoE levels. Targeting apoE should also consider the isoform- and cell type-specific effects. Another apoE-targeted therapeutic strategy is the use of small molecules that modulate apoE functions. These include peptides designed to mimic the binding site for apoE on LDL and HDL, which has been shown to increase apoE lipidation and secretion. Additionally, mimetic peptides can increase the function of apoE receptors to improve cholesterol transport. Small molecules or immunotherapies that prevent apoE self-association and/or aggregation may increase the lipid carrying capacity of apoE and reduce Aβ seeding. Similarly, modulating the lipidation of apoE has become an interesting target. Mimetic peptides can be used to increase the activity of ABCA1, which increases the lipidation of apoE4 and improves cognitive function. This can also be achieved through anti-sense oligonucleotide (ASO) inhibition of miR-33. Another promising therapeutic avenue is structural modification of apoE through genetic manipulation or small molecules. The CRISPR/Cas9 system has the potential to directly convert APOE4 to APOE3 or APOE2. This may also be achieved through an AAV system to induce apoE2 expression. A similar approach without genetic manipulation would be small molecule inhibitors to reduce interdomain interactions and structurally modify apoE to alter its function. Lastly, targeting peripheral apoE may be an alternative avenue for AD therapy. For example, plasma exchange by infusing APOE3 young plasma in APOE4 carriers is currently being tested in clinical trials to determine the beneficial effects of young plasma and the isoform-dependent effects. While these various therapeutic approaches have shown some promise in preclinical and clinical settings, they have yet to make a significant impact on the overall prognosis of AD. Research continues to seek alternative approaches to refine the current therapeutic strategies. Presently, many new technologies are being employed to discover new targets and networks such as transcriptomics, proteomics, lipidomics, and metabolomics. These multi-omics and integrative analysis may help better inform future apoE-related disease modifying therapy for AD.
Fig. 3
Fig. 3
Lifestyle changes can influence the pathogenesis of AD. ApoE4 has been shown to increase Aβ and tau aggregation, inflammation, and lipid dysregulation while reducing glucose metabolism, microbiome diversity, and BBB integrity. Healthy lifestyle changes have been suggested to benefit cognitive function and ameliorate AD pathology even in the presence of APOE4. Studies have demonstrated that ketogenic and Mediterranean diets as well as dietary supplements such as DHA can improve clinical outcomes. Along with diet, exercise has been shown to improve AD prognosis in apoE4 carriers. Chronic sleep disturbance appears to accelerate Aβ and tau pathology and exacerbate cognitive symptoms. The influence of APOE4 on sleep quality may lead to sleep disturbances in people at increased risk for dementia. Thus, improving sleep quality could reduce AD pathology and attenuate the negative impact of APOE4 on AD risk. The communication between gut microbiome and the brain, the microbiota-gut-brain axis, plays an important role in modulating AD pathology. ApoE isoforms have been shown to differentially modulate microbiome diversity. Evidence supports the use of sesamol to reshape the gut microbiome and prevent systemic inflammation. Thus, understanding the link between AD, apoE, and gut microbiota modulated through dietary approaches may offer avenues for identifying novel biomarkers and therapeutic strategies against AD

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