神经退行性疾病中的胆固醇失衡和神经传递缺陷-动脉网

Cholesterol imbalance and neurotransmission defects in neurodegeneration

Nature 等信源发布 2024-08-01 09:59

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AbstractThe brain contains the highest concentration of cholesterol in the human body, which emphasizes the importance of cholesterol in brain physiology. Cholesterol is involved in neurogenesis and synaptogenesis, and age-related reductions in cholesterol levels can lead to synaptic loss and impaired synaptic plasticity, which potentially contribute to neurodegeneration.

摘要大脑中含有人体内最高浓度的胆固醇，这强调了胆固醇在大脑生理中的重要性。。

The maintenance of cholesterol homeostasis in the neuronal plasma membrane is essential for normal brain function, and imbalances in cholesterol distribution are associated with various neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. This review aims to explore the molecular and pathological mechanisms by which cholesterol imbalance can lead to neurotransmission defects and neurodegeneration, focusing on four key mechanisms: (1) synaptic dysfunction, (2) alterations in membrane structure and protein clustering, (3) oligomers of amyloid beta (Aβ) protein, and (4) α-synuclein aggregation..

维持神经元质膜中的胆固醇稳态对于正常的大脑功能至关重要，胆固醇分布的不平衡与各种神经退行性疾病有关，包括阿尔茨海默氏病，帕金森氏病和亨廷顿氏病。本综述旨在探讨胆固醇失衡导致神经传递缺陷和神经退行性疾病的分子和病理机制，重点关注四个关键机制：（1）突触功能障碍，（2）膜结构和蛋白质聚集的改变，（3）淀粉样β（Aβ）蛋白寡聚体和（4）α-突触核蛋白聚集。。

IntroductionCholesterol is a lipid that is critical for the structure and function of cell membranes in the brain, where it participates in neuronal signaling and synaptic transmission. The brain contains the highest concentration of cholesterol in the human body, accounting for 20–25% of the total cholesterol1,2.

引言胆固醇是一种脂质，对大脑细胞膜的结构和功能至关重要，它参与神经元信号传导和突触传递。大脑含有人体内最高浓度的胆固醇，占总胆固醇的20-25%1,2。

The blood–brain barrier (BBB) is impermeable to peripheral cholesterol3; therefore, most cholesterol in the brain is generated by de novo synthesis, mainly in the glia and to a lesser extent in neurons3. The high cholesterol concentration suggests an important role for cholesterol in brain physiology.Cholesterol is involved in neurogenesis and synaptogenesis4,5.

血脑屏障（BBB）不渗透外周胆固醇3；因此，大脑中的大多数胆固醇是通过从头合成产生的，主要在神经胶质中产生，在神经元中产生的程度较小3。高胆固醇浓度表明胆固醇在大脑生理中起着重要作用。胆固醇参与神经发生和突触发生4,5。

Age-related reductions in cholesterol levels in the plasma membrane lead to synaptic loss6,7 and impaired synaptic plasticity8, suggesting that cholesterol imbalance in the neuronal plasma membrane affects neuronal activity and contributes to neuronal degeneration9,10. The maintenance of cholesterol homeostasis is essential for normal brain functions11,12,13.

与年龄相关的质膜胆固醇水平降低会导致突触丢失6,7和突触可塑性受损8，这表明神经元质膜中的胆固醇失衡会影响神经元活动并导致神经元变性9,10。维持胆固醇稳态对于正常的大脑功能至关重要11,12,13。

An imbalance in cholesterol distribution can cause the pathological changes observed in various neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), suggesting that neurodegenerative diseases are associated with dysregulated cholesterol distribution11,12,14.The aim of this review is to examine the molecular and pathological mechanisms by which cholesterol imbalance causes neurotransmission defects.

胆固醇分布不平衡可导致各种神经退行性疾病（如阿尔茨海默病（AD），帕金森病（PD）和亨廷顿舞蹈病（HD））中观察到的病理变化，这表明神经退行性疾病与胆固醇分布失调有关11,12,14。本综述的目的是研究胆固醇失衡导致神经传递缺陷的分子和病理机制。

This review focuses on four molecular mechanisms to explain how cholesterol imbalance in neurons results in neurodegeneration: (1) synaptic dysfunction, (2) membrane structure and protein clustering, (3) amyloid beta (Aβ) aggregation, and (4) α-synuclein (α-syn) aggregation.Main TextThe m.

这篇综述重点介绍了四种分子机制来解释神经元胆固醇失衡如何导致神经退行性变：（1）突触功能障碍，（2）膜结构和蛋白质聚集，（3）淀粉样β（Aβ）聚集和（4）α-突触核蛋白（α-syn）聚集。主文本m。

Synaptic dysfunction: cholesterol is critical for the formation and function of synapses, the connections between neurons that facilitate communication in the brain. Altered cholesterol levels can affect synaptic transmission and plasticity, impairing neuronal signaling and contributing to the cognitive deficits observed in neurodegenerative diseases.

突触功能障碍：胆固醇对突触的形成和功能至关重要，突触是促进大脑交流的神经元之间的连接。胆固醇水平的改变会影响突触传递和可塑性，损害神经元信号传导，并导致神经退行性疾病中观察到的认知缺陷。

The plasma membrane is enriched with cholesterol, ~80% of which is cellular cholesterol15. Therefore, reduced cholesterol levels in the plasma membrane, i.e., cholesterol imbalance, impairs synaptic transmission and plasticity and thus induces neurodegeneration9,10,16..

质膜富含胆固醇，其中约80%是细胞胆固醇15。因此，降低质膜中的胆固醇水平，即胆固醇失衡，会损害突触传递和可塑性，从而诱发神经退行性疾病9,10,16。。

Depletion and imbalance of cholesterol in the plasma membrane cause deficits in neurotransmission; e.g., cholesterol depletion reduces Ca2+-dependent exocytosis of large dense-core vesicles (LDCVs)17, cortical secretory vesicles18, and synaptic vesicles in hippocampal neurons9,19, cortical synaptosomes20, ribbon synapses21, and motor nerve terminals22.

质膜中胆固醇的消耗和失衡导致神经传递缺陷；e、例如，胆固醇消耗减少了海马神经元9,19，皮质突触体20，带状突触21和运动神经末梢22中大致密核心囊泡（LDCV）17，皮质分泌囊泡18和突触囊泡的Ca2+依赖性胞吐作用。

However, unveiling the molecular pathology of cholesterol imbalance in neurodegeneration is challenging because cholesterol is involved in various cellular signaling processes and neuronal functions. The reconstitution system of vesicle fusion with purified native vesicles, including LDCVs and synaptic vesicles, can be a good model for elucidating the molecular mechanisms by which cholesterol deficiency affects vesicle fusion23 (Fig.

。囊泡融合与纯化的天然囊泡（包括LDCV和突触囊泡）的重建系统可以作为阐明胆固醇缺乏影响囊泡融合的分子机制的良好模型23（图）。

1).Fig. 1: Schematic illustration of the roles of cholesterol in Ca2+-dependent vesicle fusion.Cholesterol is essential for Ca2+-dependent vesicle fusion. Synaptotagmin-1, a Ca2+ sensor that triggers fusion, induces local deformation of the plasma membrane. The plasma membrane is normally flexible and can return to its original shape due to membrane elasticity.

1）。图1：胆固醇在Ca2+依赖性囊泡融合中的作用的示意图。胆固醇对于Ca2+依赖性囊泡融合至关重要。。质膜通常是柔性的，并且由于膜的弹性可以恢复到其原始形状。

However, cholesterol makes the membrane less fluid and more rigid, which helps to strengthen the membrane curvature and deformation, thus lowering the energy barrier for fusion. This image was created with BioRender.com.Full size image.

然而，胆固醇使膜流动性降低，刚性增强，有助于增强膜的曲率和变形，从而降低融合的能量屏障。此图像是使用BioRender.com.Full size image创建的。

This reconstitution of vesicle fusion shows that cholesterol has little effect on Ca2+-independent basal fusion of synaptic vesicles but is required for Ca2+-dependent fusion of LDCVs and synaptic vesicles23. It is surprising that cholesterol reduction and imbalance specifically disrupt Ca2+-dependent vesicle fusion.

这种囊泡融合的重建表明，胆固醇对突触囊泡的Ca2+非依赖性基础融合几乎没有影响，但对于LDCV和突触囊泡的Ca2+依赖性融合是必需的23。令人惊讶的是，胆固醇的降低和失衡特别破坏了Ca2+依赖性囊泡融合。

Cholesterol has no effect on the membrane binding or insertion of synaptotagmin-1, a Ca2+ sensor for vesicle fusion23. Once synaptotagmin-1 is inserted into the membrane, cholesterol stabilizes and strengthens the local membrane bending and deformation induced by synaptotagmin-123. The membrane is highly flexible, so it can reform into its original shape due to membrane elasticity24.

胆固醇对突触结合蛋白-1（一种用于囊泡融合的Ca2+传感器）的膜结合或插入没有影响23。一旦突触结合蛋白-1插入膜中，胆固醇就会稳定并增强由突触结合蛋白-123诱导的局部膜弯曲和变形。该膜具有很高的柔韧性，因此由于膜的弹性，它可以重新形成原始形状24。

Because cholesterol reduces membrane fluidity and increases membrane rigidity25, cholesterol can strengthen local membrane deformation and bending, thus lowering the energy barrier for Ca2+-dependent fusion23 (Fig. 1)..

由于胆固醇会降低膜的流动性并增加膜的刚性25，因此胆固醇可以增强局部膜的变形和弯曲，从而降低Ca2+依赖性融合的能量屏障23（图1）。。

Membrane bending and curvature play crucial roles in the process of vesicle fusion by lowering the energy barrier26. The energy stored in the curvature of the membrane can be released to facilitate the merging of two separate lipid bilayers26,27,28. For instance, smaller vesicles, which have a greater curvature, have greater bending energy per unit surface area, leading to a more efficient fusion process26.

膜弯曲和曲率通过降低能量屏障在囊泡融合过程中起着至关重要的作用26。可以释放存储在膜曲率中的能量，以促进两个单独的脂质双层的合并26,27,28。例如，曲率较大的较小囊泡每单位表面积具有较大的弯曲能，从而导致更有效的融合过程26。

The insertion of proteins such as the C2AB domain of synaptotagmin-1 into the plasma membrane contributes to this curvature29,30, creating a high-energy state that can drive vesicle fusion..

将诸如突触结合蛋白-1的C2AB结构域之类的蛋白质插入质膜有助于这种曲率29,30，从而产生可以驱动囊泡融合的高能状态。。

Cholesterol enhances membrane curvature and thus lowers the energy barrier for fusion18. It also strengthens local bending and deformation, particularly in the presence of Ca2+ and synaptotagmin-1, thereby driving Ca2+-dependent vesicle fusion23. Mechanical forces of membrane bending are critical for the dynamic process of vesicle fusion31, and cholesterol is an essential lipid for synaptic transmission because it strengthens membrane bending23..

胆固醇增强膜曲率，从而降低融合的能量屏障18。它还增强了局部弯曲和变形，特别是在Ca2+和突触结合蛋白-1的存在下，从而驱动Ca2+依赖性囊泡融合23。膜弯曲的机械力对于囊泡融合的动态过程至关重要31，胆固醇是突触传递的必需脂质，因为它增强了膜的弯曲23。。

Synaptic transmission involves the release of neurotransmitters from synaptic vesicles into synapses, where neurotransmitters bind to receptors on postsynaptic neurons, thereby transmitting signals across the neural network32. When synaptic transmission is impaired due to disruptions in Ca2+-dependent vesicle fusion, neural network formation becomes impaired33.

突触传递涉及神经递质从突触小泡释放到突触中，其中神经递质与突触后神经元上的受体结合，从而通过神经网络传递信号32。当突触传递由于Ca2+依赖性囊泡融合的破坏而受损时，神经网络的形成受到损害33。

Disruption of Ca2+-dependent vesicle fusion and synaptic transmission via a cholesterol imbalance in the plasma membrane leads to reduced neural network activity and synaptic dysfunction and ultimately contributes to neurodegeneration. The loss of the neural network caused by the dysregulation of cholesterol homeostasis can result in declines in cognitive and motor functions associated with neurodegenerative diseases..

通过质膜中的胆固醇失衡破坏Ca2+依赖性囊泡融合和突触传递，导致神经网络活性降低和突触功能障碍，并最终导致神经变性。胆固醇稳态失调引起的神经网络丢失可能导致与神经退行性疾病相关的认知和运动功能下降。。

Membrane structure and protein clustering: cholesterol regulates membrane structure, fluidity, and curvature25. The plasma membrane is enriched in cholesterol15, which stabilizes membrane curvature and promotes vesicle fusion17,25,34,35. The membrane curvature and deformation stabilized by cholesterol bring the two membranes close together and enable fusion.

膜结构和蛋白质聚集：胆固醇调节膜结构，流动性和曲率25。质膜富含胆固醇15，可稳定膜曲率并促进囊泡融合17,25,34,35。胆固醇稳定的膜曲率和变形使两个膜紧密结合并实现融合。

Cholesterol also contributes to vesicle fusion by stabilizing fusion pores25,36,37,38. Therefore, cholesterol deficiency in neurons causes defects in membrane structure, resulting in neurodegeneration..

胆固醇还通过稳定融合孔25,36,37,38促进囊泡融合。因此，神经元中的胆固醇缺乏会导致膜结构缺陷，从而导致神经变性。。

Cholesterol also mediates the protein clustering involved in vesicle fusion. Exocytosis of neurotransmitter release is mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins39,40. Neuronal SNARE proteins consist of Q-SNARE in the plasma membrane (syntaxin-1 and SNAP-25) and R-SNARE in the vesicle membrane (synaptobrevin-2 or vesicle-associated membrane protein-2 (VAMP-2))39.

胆固醇还介导参与囊泡融合的蛋白质聚集。神经递质释放的胞吐作用由可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）蛋白介导39,40。。

Specialized microdomains within the plasma membrane, e.g., lipid rafts, detergent-resistant membranes, or liquid-ordered membrane microdomains, are enriched in cholesterol and concentrate signaling molecules41,42,43. Cholesterol plays an important role in the function and organization of SNARE proteins; syntaxin-1A, a neuronal SNARE protein, is concentrated in cholesterol-enriched domains in the plasma membrane44,45.

质膜内的特殊微区，例如脂筏，耐去污剂膜或液体有序膜微区，富含胆固醇并浓缩信号分子41,42,43。胆固醇在SNARE蛋白的功能和组织中起着重要作用；syntaxin-1A是一种神经元SNARE蛋白，集中在质膜中富含胆固醇的结构域44,45。

The cholesterol-enriched membrane microdomains provide a specialized environment where syntaxin-1A interacts with its binding partners. In the context of synaptic transmission, the clustering of syntaxin-1A in cholesterol-enriched microdomains may enhance its interactions with other SNARE proteins, such as SNAP-25 and VAMP-2, to form the core SNARE complex necessary for vesicle fusion.

富含胆固醇的膜微区提供了syntaxin-1A与其结合伴侣相互作用的特殊环境。在突触传递的背景下，syntaxin-1A在富含胆固醇的微区中的聚集可能会增强其与其他SNARE蛋白（例如SNAP-25和VAMP-2）的相互作用，从而形成囊泡融合所必需的核心SNARE复合物。

This organization may influence the overall stability and efficiency of neurotransmitter release at the synapse, suggesting that cholesterol imbalance leads to defects in the clustering of the vesicle fusion machinery..

该组织可能会影响突触中神经递质释放的整体稳定性和效率，这表明胆固醇失衡会导致囊泡融合机制聚集的缺陷。。

Oligomers of amyloid beta (Aβ) protein: cholesterol imbalance influences the aggregation and misfolding of proteins involved in neurodegenerative diseases, such as amyloid precursor protein (APP)46. The accumulation of Aβ plaques in the brain is a hallmark pathology of AD47,48. Aβ is derived from APP through enzymatic cleavage by the β-secretase Bace149, and cholesterol modulates the processing of APP and the generation of Aβ50,51.

淀粉样蛋白β（Aβ）蛋白的寡聚体：胆固醇失衡影响与神经退行性疾病有关的蛋白质的聚集和错误折叠，例如淀粉样前体蛋白（APP）46。大脑中Aβ斑块的积累是AD47,48的标志性病理。Aβ通过β-分泌酶Bace149的酶促切割从APP衍生而来，胆固醇调节APP的加工和Aβ50,51的产生。

High cholesterol levels can promote and accelerate the cleavage of APP by Bace1, resulting in increased Aβ production and aggregation, which contributes to the formation of toxic plaques50,51,52..

高胆固醇水平可以促进和加速Bace1对APP的切割，导致Aβ产生和聚集增加，这有助于形成有毒斑块50,51,52。。

Aβ40/Aβ42 peptides are the primary constituents of Aβ oligomers and plaques, which can be stabilized by biomolecules, including carbohydrates, nucleic acids, and lipids, e.g., cholesterol53. Extracellular cholesterol strengthens Aβ fibrils and oligomers against degradation by directly binding to Aβ53,54.

Aβ40/Aβ42肽是Aβ寡聚体和斑块的主要成分，可以通过生物分子（包括碳水化合物，核酸和脂质，例如胆固醇）来稳定。细胞外胆固醇通过直接结合Aβ53,54来增强Aβ原纤维和寡聚体的降解。

Cholesterol has been implicated in the aggregation of Aβ peptides, particularly in the formation of Aβ oligomers55,56,57. Free cholesterol interacts with specific residues in Aβ peptides, particularly Phe1955. Cholesterol binds to the aromatic side chains of the Aβ peptide, thus increasing β-sheet formation in Aβ peptide oligomers55.

胆固醇与Aβ肽的聚集有关，特别是在Aβ寡聚体的形成中55,56,57。游离胆固醇与Aβ肽中的特定残基相互作用，特别是Phe1955。胆固醇与Aβ肽的芳香侧链结合，从而增加Aβ肽寡聚体中的β-折叠形成55。

A stable interaction between cholesterol and Phe19 leads to the formation of Aβ oligomers55, suggesting that the interaction of cholesterol with Aβ contributes to the formation of toxic Aβ oligomers, which play a critical role in AD pathology57..

胆固醇和Phe19之间的稳定相互作用导致Aβ寡聚体的形成55，这表明胆固醇与Aβ的相互作用有助于形成有毒的Aβ寡聚体，这在AD病理学中起关键作用57。。

Cholesterol dramatically enhances and accelerates the onset of Aβ42 aggregation through a heterogeneous nucleation pathway58. Cholesterol imbalance and elevated extracellular levels of cholesterol can promote the production and accumulation of Aβ peptides, which induce the formation of Aβ oligomers in the brain, thus contributing to neuronal damage and cognitive decline57 (Fig.

胆固醇通过异质成核途径显着增强和加速Aβ42聚集的发生58。胆固醇失衡和细胞外胆固醇水平升高可促进Aβ肽的产生和积累，从而诱导大脑中Aβ寡聚体的形成，从而导致神经元损伤和认知能力下降57（图）。

2). Aβ monomers misfold and form β-sheet-rich oligomers that eventually impair synaptic plasticity and neuronal survival59. The direct interaction of cholesterol with Aβ can stimulate and activate toxic Aβ oligomerization, which is a critical factor in AD pathogenesis.Fig. 2: Schematic overview of cholesterol transport to promote Aβ aggregation for neurodegeneration.Cholesterol enhances and accelerates APP cleavage by Bace1, leading to increased Aβ oligomer and plaque formation.

2）。Aβ单体错误折叠并形成富含β-折叠的寡聚体，最终损害突触可塑性和神经元存活59。。图2：胆固醇转运促进神经变性Aβ聚集的示意图。胆固醇增强并加速Bace1对APP的切割，导致Aβ寡聚体和斑块形成增加。

Cholesterol binds to Aβ and increases the resistance of Aβ fibrils and oligomers to degradation. Cholesterol imbalance and high extracellular cholesterol levels can stimulate the production and accumulation of Aβ peptides, which cause Aβ oligomer formation and aggregation in the brain, resulting in neuronal damage.

胆固醇与Aβ结合并增加Aβ原纤维和寡聚体对降解的抵抗力。胆固醇失衡和高细胞外胆固醇水平可刺激Aβ肽的产生和积累，从而导致Aβ寡聚体在大脑中形成和聚集，从而导致神经元损伤。

This image was created with BioRender.com.Full size image.

此图像是使用BioRender.com.Full size image创建的。

The membrane curvature induced by cholesterol might contribute to Aβ aggregation60. High membrane curvature promotes Aβ nucleation, accelerating amyloid fibril formation61. Aβ aggregates can readily form on membranes with high curvature62. High membrane curvature, such as that associated with lipid rafts and membrane budding processes, might provide favorable conditions for the nucleation of Aβ peptides61,62,63.

胆固醇诱导的膜曲率可能有助于Aβ聚集60。高膜曲率促进Aβ成核，加速淀粉样原纤维形成61。Aβ聚集体很容易在具有高曲率的膜上形成62。高膜曲率，例如与脂筏和膜出芽过程相关的膜曲率，可能为Aβ肽的成核提供有利条件61,62,63。

Given that cholesterol stabilizes high membrane curvature, cholesterol-mediated curvature of membranes may lead to altered lipid packing that engages Aβ hydrophobic groups and promotes Aβ fibrillar structures64. Lipid packing defects that occur in curved membranes may induce conformational changes in Aβ peptides, thus promoting Aβ fibrils and aggregation64.

鉴于胆固醇稳定了高膜曲率，胆固醇介导的膜曲率可能导致脂质堆积改变，从而与Aβ疏水基团结合并促进Aβ纤维结构64。弯曲膜中发生的脂质堆积缺陷可能会诱导Aβ肽的构象变化，从而促进Aβ原纤维和聚集64。

This aggregation is a hallmark of AD, and understanding the underlying mechanisms of membrane curvature is crucial for developing potential therapeutic strategies. The interplay between membrane curvature and Aβ aggregation is complex, and ongoing research continues to unveil the molecular details involved..

这种聚集是AD的标志，了解膜曲率的潜在机制对于开发潜在的治疗策略至关重要。膜曲率和Aβ聚集之间的相互作用是复杂的，正在进行的研究继续揭示所涉及的分子细节。。

Tau aggregation: while Aβ oligomers and aggregation are primarily associated with AD, another hallmark of AD is the aggregation of hyperphosphorylated tau proteins into neurofibrillary tangles (NFTs)65. Tau is a cytoskeletal protein that stabilizes microtubules in neurons, but it is hyperphosphorylated in AD66.

。Tau是一种稳定神经元微管的细胞骨架蛋白，但在AD66中被过度磷酸化。

The interaction between tau proteins and cell membranes, particularly in cholesterol-rich regions, is a critical factor in the tau aggregation process67,68. The membrane binding of tau can induce conformational changes and aggregation with β-sheet-rich structures69. NFTs in AD brains contain cholesterol54,70, which could modulate tau-membrane interactions and affect tau aggregation68,71..

tau蛋白与细胞膜之间的相互作用，特别是在富含胆固醇的区域，是tau聚集过程中的关键因素67,68。tau的膜结合可以诱导构象变化和富含β-折叠结构的聚集69。AD大脑中的NFT含有胆固醇54,70，它可以调节tau膜相互作用并影响tau聚集68,71。。

As cholesterol can influence membrane curvature, high membrane curvature caused by cholesterol can induce changes in the conformation of tau proteins and promote tau aggregation72. Membranes with high curvature that contain cholesterol induce tau fibril formation, whereas cholesterol depletion abolishes tau fibril formation72.

由于胆固醇可以影响膜曲率，由胆固醇引起的高膜曲率可以诱导tau蛋白构象的变化并促进tau聚集72。含有胆固醇的高曲率膜诱导tau原纤维形成，而胆固醇消耗消除了tau原纤维形成72。

Cholesterol-free membranes fail to induce the formation of tau fibrils, suggesting that cholesterol-mediated tau aggregation is essential for the pathology of tauopathies72. Membrane morphologies result in different hydrophobic interactions that lead to the β-sheet structures of tau proteins72. The association of tau with highly curved membranes is initiated by electrostatic attraction between the Lys sidechains of tau and the lipid headgroups; cholesterol might further strengthen this electrostatic attraction for tau fibril formation72.

。膜形态导致不同的疏水相互作用，导致tau蛋白的β-折叠结构72。tau与高度弯曲的膜的缔合是由tau的Lys侧链与脂质头基之间的静电吸引引起的；胆固醇可能会进一步增强这种对tau原纤维形成的静电吸引力72。

However, how cholesterol facilitates tau nucleation remains a topic of further study, and understanding the underlying molecular mechanisms is crucial for developing therapeutic strategies involving the disruption of tau aggregation..

然而，胆固醇如何促进tau成核仍然是进一步研究的主题，了解潜在的分子机制对于开发涉及tau聚集破坏的治疗策略至关重要。。

α-Synuclein (α-syn) aggregation: a characteristic feature of PD is the accumulation of misfolded α-syn proteins in Lewy bodies (LBs)73. The interaction between α-syn and lipids is important for fibril formation, and the aggregation of α-syn is induced by binding to membrane lipids74. Lipids dramatically enhance the primary nucleation of α-syn to form aggregates associated with neurodegeneration74..

α-突触核蛋白（α-syn）聚集：PD的一个特征是路易体（LBs）中错误折叠的α-syn蛋白的积累73。α-syn和脂质之间的相互作用对于原纤维形成很重要，α-syn的聚集是通过与膜脂质结合而诱导的74。脂质显着增强α-syn的初级成核，形成与神经退行性变相关的聚集体74。。

Table 1 Cholesterol and neurodegenerative diseases.Full size tableTogether with α-syn, cholesterol, which is a component of LBs75, accelerates α-syn aggregation and LB formation76. Cholesterol interacts with α-syn, and high cholesterol levels can promote α-syn aggregation76,77, leading to the formation of toxic LBs, which contributes to neurodegeneration in PD.α-Syn binds to membranes through electrostatic interactions and hydrogen bonding, but cholesterol reduces the coulomb interactions and hydrophobic interactions between α-syn and membranes78.

表1胆固醇和神经退行性疾病。全尺寸表与LBs75的组成部分α-syn，胆固醇一起加速α-syn聚集和LB形成76。胆固醇与α-syn相互作用，高胆固醇水平可促进α-syn聚集76,77，导致有毒LB的形成，这有助于PD的神经变性。α-syn通过静电相互作用和氢键与膜结合，但胆固醇降低了α-syn与膜之间的库仑相互作用和疏水相互作用78。

Cholesterol decreases lipid packing defects and lipid fluidity, thereby dysregulating the membrane binding of α-syn78; membrane-bound α-syn can have a β-sheet structure that induces the formation of toxic α-syn oligomers and fibrils. Together, the imbalance and dysregulated distribution of cholesterol in neurons cause neurodegeneration by accelerating α-syn aggregation and LB formation.Possible therapeutic approaches for cholesterol imbalanceThe apolipoprotein E (ApoE) gene is involved in the metabolism and transport of cholesterol79,80.

；膜结合的α-syn可以具有β-折叠结构，诱导形成有毒的α-syn低聚物和原纤维。总之，胆固醇在神经元中的不平衡和失调分布通过加速α-syn聚集和LB形成而引起神经变性。胆固醇不平衡的可能治疗方法载脂蛋白E（ApoE）基因参与胆固醇的代谢和转运79,80。

There are three main variants or alleles of the APOE gene, namely, ApoE2, ApoE3, and ApoE481. The ApoE4 protein is the most important risk factor for late-onset AD82, i.e., the most common form of the disease that occurs after age 65. The molecular mechanisms by which ApoE4 contributes to AD are complex and not fully understood, but ApoE4 likely promotes Aβ aggregation by transporting cholesterol79,83.

APOE基因有三个主要变体或等位基因，即ApoE2，ApoE3和ApoE481。ApoE4蛋白是迟发性AD82的最重要危险因素，即65岁以后发生的最常见疾病。ApoE4促进AD的分子机制很复杂，尚不完全清楚，但ApoE4可能通过转运胆固醇促进Aβ聚集79,83。

ApoE4 can induce cholesterol imbalance by transporting cholesterol from the plasma membrane in neurons to protein aggregates (Fig. 2). Given that cholesterol imbalance causes neurodegeneration, ApoE4 may be a possible target for mitigating Aβ aggregation and treating cholesterol imbalance.Overal.

ApoE4可以通过将胆固醇从神经元的质膜转运到蛋白质聚集体来诱导胆固醇失衡（图2）。鉴于胆固醇失衡会导致神经变性，ApoE4可能是减轻aβ聚集和治疗胆固醇失衡的可能靶标。总体。

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Download referencesAcknowledgementsThis work was supported by grants from the Qatar Biomedical Research Institute (Project Number SF 2019 004 and IGP5-2022-001 to Y.P.) and the HBKU Thematic Research Grant (Project Number VPR-TG02-06 to Y.P.).Author informationAuthors and AffiliationsNeurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, QatarKyung Chul Shin, Houda Yasmine Ali Moussa & Yongsoo ParkCollege of Health & Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, QatarYongsoo ParkAuthorsKyung Chul ShinView author publicationsYou can also search for this author in.

下载参考文献致谢这项工作得到了卡塔尔生物医学研究所（项目编号SF 2019 004和IGP5-2022-001至Y.P.）和HBKU主题研究资助（项目编号VPR-TG02-06至Y.P.）的资助。作者信息作者和附属机构卡塔尔生物医学研究所（QBRI），哈马德·本·哈利法大学（HBKU），卡塔尔基金会，多哈，卡塔尔中央新，侯达亚斯敏·阿里·穆萨和永寿公园健康与生命科学学院（CHLS），哈马德·本·哈利法大学（HBKU），卡塔尔基金会，多哈，卡塔尔中央公园作者Kyung Chul ShinView作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarHouda Yasmine Ali MoussaView author publicationsYou can also search for this author in

PubMed Google ScholarHouda Yasmine Ali MoussaView作者出版物您也可以在

PubMed Google ScholarYongsoo ParkView author publicationsYou can also search for this author in

PubMed Google ScholarYongsoo ParkView作者出版物您也可以在

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Reprints and permissionsAbout this articleCite this articleShin, K.C., Ali Moussa, H.Y. & Park, Y. Cholesterol imbalance and neurotransmission defects in neurodegeneration.

转载和许可本文引用本文Shin，K.C.，Ali Moussa，H.Y。＆Park，Y。神经退行性疾病中的胆固醇失衡和神经传递缺陷。

Exp Mol Med (2024). https://doi.org/10.1038/s12276-024-01273-4Download citationReceived: 24 October 2023Revised: 16 April 2024Accepted: 18 April 2024Published: 01 August 2024DOI: https://doi.org/10.1038/s12276-024-01273-4Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

Exp Mol Med（2024）。https://doi.org/10.1038/s12276-024-01273-4Download引文接收日期：2023年10月24日修订日期：2024年4月16日接受日期：2024年4月18日发布日期：2024年8月1日OI：https://doi.org/10.1038/s12276-024-01273-4Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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