Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer’s disease?

Abstract

Human apolipoprotein E (ApoE) is a 299-amino acid secreted glycoprotein that binds cholesterol and phospholipids. ApoE exists as three common isoforms (ApoE2, ApoE3, and ApoE4) and heterozygous carriers of the ε4 allele of the gene encoding ApoE ( APOE) have a fourfold greater risk of developing Alzheimer’s disease (AD). The enzymes thrombin, cathepsin D, α-chymotrypsin-like serine protease, and high-temperature requirement serine protease A1 are responsible for ApoE proteolytic processing resulting in bioactive C-terminal-truncated fragments that vary depending on ApoE isoforms, brain region, aging, and neural injury. The objectives of the present narrative review were to describe ApoE processing, discussing current hypotheses about the potential role of various ApoE fragments in AD pathophysiology, and reviewing the current development status of different anti-ApoE drugs. The exact mechanism by which APOE gene variants increase/decrease AD risk and the role of ApoE fragments in the deposition are not fully understood, but APOE is known to directly affect tau-mediated neurodegeneration. ApoE fragments co-localize with neurofibrillary tangles and amyloid β (Aβ) plaques, and may cause neurodegeneration. Among anti-ApoE approaches, a fascinating strategy may be to therapeutically overexpress ApoE2 in APOE ε4/ε4 carriers through vector administration or liposomal delivery systems. Another approach involves reducing ApoE4 expression by intracerebroventricular antisense oligonucleotides that significantly decreased Aβ pathology in transgenic mice. Differences in the proteolytic processing of distinct ApoE isoforms and the use of ApoE fragments as mimetic peptides in AD treatment are also under investigation. Treatment with peptides that mimic the structural and biological properties of native ApoE may reduce Aβ deposition, tau hyperphosphorylation, and glial activation in mouse models of Aβ pathology. Alternative strategies involve the use of ApoE4 structure correctors, passive immunization to target a certain form of ApoE, conversion of the ApoE4 aminoacid sequence into that of ApoE3 or ApoE2, and inhibition of the ApoE-Aβ interaction.

Estudio molecular de los polimorfismos comunes del gen apoE asociados con disbetalipoproteinemia familiar y la enfermedad de Alzheimer de inicio tardío

“…The APOE allele frequencies in the Chinese Han population, which were collected from the Chaozhou region, were 7.0% for ε2, 87.5% for ε3 and 5.5% for ε4. Compared with other Chinese populations (Table III) (18)(19)(20)(21)(22), the APOE gene allele frequencies of the study population were most similar to those of a Taiwanese population (20), but significantly different from those of the Chinese minority ethnic groups: The Uygur population in the Xinjiang Uygur Autonomous Region (22), the Li population on Hainan Island (18) and the Zhuang population in the Guangxi Zhuang Autonomous Region (19). A number of A) Análisis de la Tm (temperatura de "melting"o de fusión del ADN) para el producto de amplificación correspondiente a rs429358.…”

“…También se une e interactúa con componentes inflamatorios como los lipopolisacaridos (LPS), beta-amiloide (Aß), beta-glucanos y ácidos lipoteicoico. Se cree que esta función facilita la eliminación de moléculas inflamatorias y patógenas, lo que sugiere un papel de apoE en la inmunidad innata 16,18 .…”

Blood–Brain Barrier Breakdown in Alzheimer’s Disease: Mechanisms and Targeted Strategies

“…ApoE amino acids vary at locations 112 and 158 on chromosome 19, and there are six different genotypes, i.e., three homozygous and three heterozygous [76]. ApoEε2 is protective against the pathology of AD [77]. ApoEε2 expression clears Aβ normally and may suppress inflammation, which can protect against AD [76].…”

Effect of thymol on oxidative stress and reelin signaling pathway in Alzheimer's disease model

“…There are three common isoforms in humans, ApoE2, ApoE3, and ApoE4 ( Knopman et al, 2021 ). Heterozygous carriers of the ɛ4 allele of the gene encoding ApoE are four times more likely to develop Alzheimer’s disease ( Vecchio et al, 2022 ). ApoE4 increases beta-amyloid aggregation, contributing to neurofibrillary tangle formation and the pathogenesis of AD through processes such as neuroinflammation and synaptic loss ( Mamun et al, 2020 ).…”