Vecchio Filomena Lo, Bisceglia Paola, Imbimbo Bruno Pietro, Lozupone Madia, Latino Raffaela Rita, Resta Emanuela, Leone Maurizio, Solfrizzi Vincenzo, Greco Antonio, Daniele Antonio, Watling Mark, Panza Francesco, Seripa Davide
Research Laboratory, Complex Structure of Geriatrics, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia 71013, Italy.
Research Laboratory, Complex Structure of Geriatrics, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Ther Adv Chronic Dis. 2022 Mar 17;13:20406223221081605. doi: 10.1177/20406223221081605. eCollection 2022.
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 allele of the gene encoding 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 gene variants increase/decrease AD risk and the role of ApoE fragments in the deposition are not fully understood, but 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 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.
人类载脂蛋白E（ApoE）是一种由299个氨基酸组成的分泌型糖蛋白，可结合胆固醇和磷脂。ApoE以三种常见的异构体形式（ApoE2、ApoE3和ApoE4）存在，编码ApoE（）基因的等位基因杂合携带者患阿尔茨海默病（AD）的风险高出四倍。凝血酶、组织蛋白酶D、α-糜蛋白酶样丝氨酸蛋白酶和高温需求丝氨酸蛋白酶A1负责ApoE的蛋白水解加工，产生具有生物活性的C末端截短片段，这些片段因ApoE异构体、脑区、衰老和神经损伤而异。本叙述性综述的目的是描述ApoE的加工过程，讨论当前关于各种ApoE片段在AD病理生理学中潜在作用的假说，并综述不同抗ApoE药物的当前研发状况。基因变异增加/降低AD风险的确切机制以及ApoE片段在沉积中的作用尚未完全了解，但已知其直接影响tau介导的神经变性。ApoE片段与神经原纤维缠结和淀粉样β（Aβ）斑块共定位，并可能导致神经变性。在抗ApoE方法中，一种引人入胜的策略可能是通过载体给药或脂质体递送系统在携带者中治疗性过表达ApoE2。另一种方法是通过脑室内反义寡核苷酸降低ApoE4表达，这可显著降低转基因小鼠中的Aβ病理。不同ApoE异构体的蛋白水解加工差异以及在AD治疗中使用ApoE片段作为模拟肽的研究也在进行中。用模拟天然ApoE结构和生物学特性的肽进行治疗可能会减少Aβ病理小鼠模型中的Aβ沉积、tau过度磷酸化和神经胶质细胞激活。其他策略包括使用ApoE4结构校正剂、针对某种形式的ApoE进行被动免疫、将ApoE4氨基酸序列转化为ApoE3或ApoE2的序列以及抑制ApoE-Aβ相互作用。
