神经认知障碍的神经精神症状和载脂蛋白E基因型。

IF 5.9 2区 医学 Q2 CELL BIOLOGY
Neural Regeneration Research Pub Date : 2026-04-01 Epub Date: 2025-03-25 DOI:10.4103/NRR.NRR-D-24-01274
Madia Lozupone, Ivana Leccisotti, Anita Mollica, Giuseppe Berardino, Maria Claudia Moretti, Mario Altamura, Antonello Bellomo, Antonio Daniele, Vittorio Dibello, Vincenzo Solfrizzi, Emanuela Resta, Francesco Panza
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引用次数: 0

摘要

神经退行性疾病和神经精神症状之间存在复杂的遗传关系,提示了共同的致病机制,并强调了开发共同治疗靶点的潜力。载脂蛋白E (APOE)基因型及其相应的蛋白(APOE)亚型可能影响细胞膜脂质双分子层的生物物理特性。然而,APOE在中枢神经系统病理生理中的作用超出了其脂质转运功能。在这篇综述文章中,我们分析了APOE基因型与神经退行性疾病和血管疾病神经精神症状的神经生物学之间存在的联系。APOE基因型(APOE ε2、APOE ε3和APOE ε4)与广泛的神经退行性疾病的共同机制有关,包括散发性阿尔茨海默病、突触核蛋白病(如帕金森病和路易体病)、中风和创伤性脑损伤。这些共享通路通常涉及神经炎症、异常蛋白积累或对急性有害事件的反应。在这些情况下,APOE变异被认为有助于炎症反应的调节,淀粉样蛋白和tau病理的调节,以及α-突触核蛋白等蛋白质的清除。APOE、淀粉样蛋白和线粒体代谢、免疫调节作用、神经元修复和重塑之间的双向相互作用强调了APOE在与这些疾病相关的神经精神症状中的作用的复杂性,这些症状始于认知障碍的早期阶段,如轻度认知障碍和轻度行为障碍。除了APOE特异性亚型与阿尔茨海默病的神经精神症状(抑郁、精神病、异常运动行为和焦虑,而不是冷漠)增加有关外,APOE ε4基因型也被认为是路易体病及其较差认知结果的重要遗传危险因素。相反,APOE ε2变异在所有神经退行性疾病中并没有发挥同等的保护作用。具体来说,在路易体病中,这种变异可能延迟疾病的发作,与其在阿尔茨海默病中的保护作用类似,尽管其在额颞叶痴呆中的作用尚不确定。APOE ε4基因型与其他各种神经退行性疾病的不良认知结果有关。在帕金森氏症中,APOE ε4等位基因显著影响认知能力,增加患痴呆症的风险,即使是纯突触核蛋白病,阿尔茨海默病的共同病理也不例外。同样,在创伤性脑损伤中,恢复率各不相同,APOE ε4携带者表现出较差的长期认知结果和较高水平的神经精神症状的风险。此外,APOE ε4影响中风的发病年龄和严重程度,以及发生中风相关痴呆的可能性,可能是由于它在损害内皮完整性和促进血脑屏障功能障碍中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Neuropsychiatric symptoms and apolipoprotein E genotypes in neurocognitive disorders.

Complex genetic relationships between neurodegenerative disorders and neuropsychiatric symptoms have been shown, suggesting shared pathogenic mechanisms and emphasizing the potential for developing common therapeutic targets. Apolipoprotein E ( APOE ) genotypes and their corresponding protein (ApoE) isoforms may influence the biophysical properties of the cell membrane lipid bilayer. However, the role of APOE in central nervous system pathophysiology extended beyond its lipid transport function. In the present review article, we analyzed the links existing between APOE genotypes and the neurobiology of neuropsychiatric symptoms in neurodegenerative and vascular diseases. APOE genotypes ( APOE ε2, APOE ε3, and APOE ε4) were implicated in common mechanisms underlying a wide spectrum of neurodegenerative diseases, including sporadic Alzheimer's disease, synucleinopathies such as Parkinson's disease and Lewy body disease, stroke, and traumatic brain injury. These shared pathways often involved neuroinflammation, abnormal protein accumulation, or responses to acute detrimental events. Across these conditions, APOE variants are believed to contribute to the modulation of inflammatory responses, the regulation of amyloid and tau pathology, as well as the clearance of proteins such as α-synuclein. The bidirectional interactions among ApoE, amyloid and mitochondrial metabolism, immunomodulatory effects, neuronal repair, and remodeling underscored the complexity of ApoE's role in neuropsychiatric symptoms associated with these conditions since from early phases of cognitive impairment such as mild cognitive impairment and mild behavioral impairment. Besides ApoE-specific isoforms' link to increased neuropsychiatric symptoms in Alzheimer's disease (depression, psychosis, aberrant motor behaviors, and anxiety, not apathy), the APOE ε4 genotype was also considered a significant genetic risk factor for Lewy body disease and its worse cognitive outcomes. Conversely, the APOE ε2 variant has been observed not to exert a protective effect equally in all neurodegenerative diseases. Specifically, in Lewy body disease, this variant may delay disease onset, paralleling its protective role in Alzheimer's disease, although its role in frontotemporal dementia is uncertain. The APOE ε4 genotype has been associated with adverse cognitive outcomes across other various neurodegenerative conditions. In Parkinson's disease, the APOE ε4 allele significantly impacted cognitive performance, increasing the risk of developing dementia, even in cases of pure synucleinopathies with minimal co-pathology from Alzheimer's disease. Similarly, in traumatic brain injury, recovery rates varied, with APOE ε4 carriers demonstrating a greater risk of poor long-term cognitive outcomes and elevated levels of neuropsychiatric symptoms. Furthermore, APOE ε4 influenced the age of onset and severity of stroke, as well as the likelihood of developing stroke-associated dementia, potentially due to its role in compromising endothelial integrity and promoting blood-brain barrier dysfunction.

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来源期刊
Neural Regeneration Research
Neural Regeneration Research CELL BIOLOGY-NEUROSCIENCES
CiteScore
8.00
自引率
9.80%
发文量
515
审稿时长
1.0 months
期刊介绍: Neural Regeneration Research (NRR) is the Open Access journal specializing in neural regeneration and indexed by SCI-E and PubMed. The journal is committed to publishing articles on basic pathobiology of injury, repair and protection to the nervous system, while considering preclinical and clinical trials targeted at improving traumatically injuried patients and patients with neurodegenerative diseases.
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