
==== Front
Exp Mol Med
Exp Mol Med
Experimental & Molecular Medicine
1226-3613
2092-6413
Nature Publishing Group UK London

39085348
1273
10.1038/s12276-024-01273-4
Review Article
Cholesterol imbalance and neurotransmission defects in neurodegeneration
http://orcid.org/0000-0003-3684-4005
Shin Kyung Chul 1
Ali Moussa Houda Yasmine 1
Park Yongsoo ypark@hbku.edu.qa

12
1 grid.418818.c 0000 0001 0516 2170 Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
2 grid.418818.c 0000 0001 0516 2170 College of Health & Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha, Qatar
1 8 2024
1 8 2024
8 2024
56 8 16851690
24 10 2023
16 4 2024
18 4 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
The 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. 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.

Exploring Cholesterol Imbalance: Link to Neurodegenerative Diseases

Cholesterol, a substance crucial for the brain, can lead to diseases like Alzheimer’s and Parkinson’s when imbalanced. This review investigates how this imbalance causes brain cell degeneration, focusing on issues like communication breakdown and harmful protein build-up. The study combines findings from different experiments to understand cholesterol’s role in the brain. The review emphasizes the need for cholesterol balance for brain health and identifies potential treatment targets for neurodegenerative diseases. The main findings suggest that cholesterol imbalance disrupts brain cell communication and leads to harmful protein build-up, causing brain cell degeneration. The researchers conclude that focusing on cholesterol metabolism and distribution could lead to new treatments for these conditions. Future research may lead to treatments that correct cholesterol imbalances, possibly slowing or preventing neurodegenerative diseases.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

Subject terms

Synaptic vesicle exocytosis
Neurodegeneration
issue-copyright-statement© Korean Society for Biochemical and Molecular Biology 2024
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pmcIntroduction

Cholesterol 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. 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. 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 functions11–13. 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. 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 Text

The molecular mechanisms of neurodegeneration induced by cholesterol imbalance

Cholesterol has a complex and multifaceted role in neurodegeneration. Given that cholesterol is an essential component of cell membranes and is involved in various physiological processes in the brain, an imbalance and dysregulation of cholesterol homeostasis can contribute to the pathogenesis of neurodegenerative diseases11,12,14. Table 1 summarizes the links between cholesterol and different neurodegenerative diseases. Several mechanisms have been proposed to explain how cholesterol imbalance may contribute to neurodegeneration: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. 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.

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. 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. 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. 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.

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. 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. 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).

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 bilayers26–28. For instance, smaller vesicles, which have a greater curvature, have greater bending energy per unit surface area, leading to a more efficient fusion process26. 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.

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.

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. 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.

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

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. 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 molecules41–43. 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. 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. 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.

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. 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 plaques50–52.

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. Cholesterol has been implicated in the aggregation of Aβ peptides, particularly in the formation of Aβ oligomers55–57. 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. 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.

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

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 peptides61–63. 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. 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.

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. 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.

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. 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. 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.

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.

Table 1 Cholesterol and neurodegenerative diseases.

Neurodegenerative disease	Relation to cholesterol	Refs.	
Alzheimer’s Disease	High cholesterol promotes the cleavage of APP by Bace1, resulting in Aβ production and aggregation.	50–52	
Cholesterol is the primary constituent of Aβ oligomers and plaques.	53	
Cholesterol strengthens Aβ fibrils and oligomers against degradation by directly binding to Aβ.	53,54	
Cholesterol leads to the formation of Aβ oligomers through interaction with Phe19 of Aβ, thus stabilizing Aβ oligomers.	55–57	
Membrane curvature induced by cholesterol accelerates Aβ aggregation.	60–64	
ApoE4, a major risk factor for AD, is associated with dysregulation of cholesterol transport.	46	
Cholesterol stimulates tau aggregation process through tau conformational changes into β-sheet-rich structures.	54,67–71	
Cholesterol-containing membranes with high curvature induce tau fibril formation.	72	
Parkinson’s Disease	Cholesterol is a component of LBs together with α-syn.	75	
Cholesterol accelerates α-syn aggregation and LB formation.	76	
Cholesterol induces toxic α-syn oligomers and fibrils by forming β-sheet structures.	78	
Huntington’s Disease	Mutant huntingtin (mHTT) aggregates in HD and reduces nuclear translocation of the sterol regulatory element-binding protein 2 (SREBP2).	85	
Cholesterol modulates mHTT aggregation by regulating membrane interactions.	86,87	
Multiple Sclerosis (MS)	Disrupted cholesterol metabolism is associated with MS, and cholesterol induces misfolded protein aggregation.	88	

Together 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. 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 imbalance

The apolipoprotein E (ApoE) gene is involved in the metabolism and transport of cholesterol79,80. 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. 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.

Overall, the maintenance of cholesterol homeostasis is important for preventing or slowing the pathogenesis of neurodegenerative diseases. Strategies aimed at regulating cholesterol levels or targeting cholesterol-mediated pathways involved in protein aggregation might be potential therapeutic approaches to treating neurodegenerative diseases, although neurodegenerative diseases are complex and cholesterol imbalance is one of many contributing factors11,84.

Conclusion

Cholesterol is an essential component of the body that helps maintain the integrity of cell membranes. The role of cholesterol dysregulation in neurodegeneration is an active area of research, and the precise mechanisms involved may vary depending on the specific condition. The balance between the beneficial and detrimental effects of cholesterol remains complex. An imbalance in cholesterol regulation is a common feature of neurodegenerative conditions such as AD and PD. Therapeutic approaches for modulating cholesterol metabolism or targeting specific cholesterol-related pathways could be potential strategies for mitigating neurodegeneration. While cholesterol-lowering drugs, e.g., statins, have shown some potential in reducing the risk of certain neurodegenerative diseases, further research is required to fully understand the role of cholesterol and develop targeted therapeutic interventions.

Acknowledgements

This 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.).

Competing interests

The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Dietschy JM Turley SD Cholesterol metabolism in the brain Curr. Opin. Lipidol. 2001 12 105 112 11264981
Dietschy, J. M. & Turley, S. D. Cholesterol metabolism in the brain. Curr. Opin. Lipidol. 12, 105–112 (2001).11264981
2. Bjorkhem I Meaney S Brain cholesterol: long secret life behind a barrier Arterioscler. Thromb. Vasc. Biol. 2004 24 806 815 14764421
Bjorkhem, I. & Meaney, S. Brain cholesterol: long secret life behind a barrier. Arterioscler. Thromb. Vasc. Biol. 24, 806–815 (2004).14764421
3. Dietschy JM Turley SD Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal J. Lipid Res. 2004 45 1375 1397 15254070
Dietschy, J. M. & Turley, S. D. Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J. Lipid Res. 45, 1375–1397 (2004).15254070
4. Pfrieger FW Cholesterol homeostasis and function in neurons of the central nervous system Cell. Mol. Life Sci. 2003 60 1158 1171 12861382
Pfrieger, F. W. Cholesterol homeostasis and function in neurons of the central nervous system. Cell. Mol. Life Sci. 60, 1158–1171 (2003).12861382
5. Cartocci V Servadio M Trezza V Pallottini V Can cholesterol metabolism modulation affect brain function and behavior? J. Cell Physiol. 2017 232 281 286 27414240
Cartocci, V., Servadio, M., Trezza, V. & Pallottini, V. Can cholesterol metabolism modulation affect brain function and behavior? J. Cell Physiol. 232, 281–286 (2017).27414240
6. Svennerholm L Bostrom K Jungbjer B Olsson L Membrane lipids of adult human brain: lipid composition of frontal and temporal lobe in subjects of age 20 to 100 years J. Neurochem. 1994 63 1802 1811 7931336
Svennerholm, L., Bostrom, K., Jungbjer, B. & Olsson, L. Membrane lipids of adult human brain: lipid composition of frontal and temporal lobe in subjects of age 20 to 100 years. J. Neurochem. 63, 1802–1811 (1994).7931336
7. Martin M Dotti CG Ledesma MD Brain cholesterol in normal and pathological aging Biochim. Biophys. Acta 2010 1801 934 944 20359547
Martin, M., Dotti, C. G. & Ledesma, M. D. Brain cholesterol in normal and pathological aging. Biochim. Biophys. Acta 1801, 934–944 (2010).20359547
8. Martin MG Constitutive hippocampal cholesterol loss underlies poor cognition in old rodents EMBO Mol. Med. 2014 6 902 917 24878762
Martin, M. G. et al. Constitutive hippocampal cholesterol loss underlies poor cognition in old rodents. EMBO Mol. Med. 6, 902–917 (2014).24878762
9. Linetti A Cholesterol reduction impairs exocytosis of synaptic vesicles J. Cell Sci. 2010 123 595 605 20103534
Linetti, A. et al. Cholesterol reduction impairs exocytosis of synaptic vesicles. J. Cell Sci. 123, 595–605 (2010).20103534
10. Liu Q Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration J. Neurosci. 2010 30 17068 17078 21159977
Liu, Q. et al. Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, age-dependent synapse loss and neurodegeneration. J. Neurosci. 30, 17068–17078 (2010).21159977
11. Vance JE Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases Dis. Model Mech. 2012 5 746 755 23065638
Vance, J. E. Dysregulation of cholesterol balance in the brain: contribution to neurodegenerative diseases. Dis. Model Mech. 5, 746–755 (2012).23065638
12. Dai L Cholesterol metabolism in neurodegenerative diseases: molecular mechanisms and therapeutic targets Mol. Neurobiol. 2021 58 2183 2201 33411241
Dai, L. et al. Cholesterol metabolism in neurodegenerative diseases: molecular mechanisms and therapeutic targets. Mol. Neurobiol. 58, 2183–2201 (2021).33411241
13. Yoon JH Brain lipidomics: from functional landscape to clinical significance Sci. Adv. 2022 8 eadc9317 36112688
Yoon, J. H. et al. Brain lipidomics: from functional landscape to clinical significance. Sci. Adv. 8, eadc9317 (2022).36112688
14. Varma VR Abnormal brain cholesterol homeostasis in Alzheimer’s disease-a targeted metabolomic and transcriptomic study NPJ Aging Mech. Dis. 2021 7 11 34075056
Varma, V. R. et al. Abnormal brain cholesterol homeostasis in Alzheimer’s disease-a targeted metabolomic and transcriptomic study. NPJ Aging Mech. Dis. 7, 11 (2021).34075056
15. Lange Y Steck TL Active membrane cholesterol as a physiological effector Chem. Phys. Lipids 2016 199 74 93 26874289
Lange, Y. & Steck, T. L. Active membrane cholesterol as a physiological effector. Chem. Phys. Lipids 199, 74–93 (2016).26874289
16. Koudinov AR Koudinova NV Essential role for cholesterol in synaptic plasticity and neuronal degeneration FASEB J. 2001 15 1858 1860 11481254
Koudinov, A. R. & Koudinova, N. V. Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 15, 1858–1860 (2001).11481254
17. Zhang J Xue R Ong WY Chen P Roles of cholesterol in vesicle fusion and motion Biophys. J. 2009 97 1371 1380 19720025
Zhang, J., Xue, R., Ong, W. Y. & Chen, P. Roles of cholesterol in vesicle fusion and motion. Biophys. J. 97, 1371–1380 (2009).19720025
18. Churchward MA Rogasevskaia T Hofgen J Bau J Coorssen JR Cholesterol facilitates the native mechanism of Ca2+-triggered membrane fusion J. Cell Sci. 2005 118 4833 4848 16219690
Churchward, M. A., Rogasevskaia, T., Hofgen, J., Bau, J. & Coorssen, J. R. Cholesterol facilitates the native mechanism of Ca2+-triggered membrane fusion. J. Cell Sci. 118, 4833–4848 (2005).16219690
19. Mailman T Hariharan M Karten B Inhibition of neuronal cholesterol biosynthesis with lovastatin leads to impaired synaptic vesicle release even in the presence of lipoproteins or geranylgeraniol J. Neurochem. 2011 119 1002 1015 21899539
Mailman, T., Hariharan, M. & Karten, B. Inhibition of neuronal cholesterol biosynthesis with lovastatin leads to impaired synaptic vesicle release even in the presence of lipoproteins or geranylgeraniol. J. Neurochem. 119, 1002–1015 (2011).21899539
20. Teixeira G Vieira LB Gomez MV Guatimosim C Cholesterol as a key player in the balance of evoked and spontaneous glutamate release in rat brain cortical synaptosomes Neurochem. Int. 2012 61 1151 1159 22940694
Teixeira, G., Vieira, L. B., Gomez, M. V. & Guatimosim, C. Cholesterol as a key player in the balance of evoked and spontaneous glutamate release in rat brain cortical synaptosomes. Neurochem. Int. 61, 1151–1159 (2012).22940694
21. Mercer AJ Szalewski RJ Jackman SL Van Hook MJ Thoreson WB Regulation of presynaptic strength by controlling Ca2+ channel mobility: effects of cholesterol depletion on release at the cone ribbon synapse J. Neurophysiol. 2012 107 3468 3478 22442573
Mercer, A. J., Szalewski, R. J., Jackman, S. L., Van Hook, M. J. & Thoreson, W. B. Regulation of presynaptic strength by controlling Ca2+ channel mobility: effects of cholesterol depletion on release at the cone ribbon synapse. J. Neurophysiol. 107, 3468–3478 (2012).22442573
22. Tarakanova OI Petrov AM Zefirov AL The role of membrane cholesterol in neurotransmitter release from motor nerve terminals Dokl. Biol. Sci.: Proc. Acad. Sci. USSR, Biol. Sci. Sect. 2011 438 138 140
Tarakanova, O. I., Petrov, A. M. & Zefirov, A. L. The role of membrane cholesterol in neurotransmitter release from motor nerve terminals. Dokl. Biol. Sci.: Proc. Acad. Sci. USSR, Biol. Sci. Sect. 438, 138–140 (2011).
23. Ali Moussa HY Requirement of cholesterol for calcium-dependent vesicle fusion by strengthening synaptotagmin-1-induced membrane bending Adv. Sci. 2023 10 e2206823
Ali Moussa, H. Y. et al. Requirement of cholesterol for calcium-dependent vesicle fusion by strengthening synaptotagmin-1-induced membrane bending. Adv. Sci. 10, e2206823 (2023).
24. Lipowsky R Remodeling of membrane shape and topology by curvature elasticity and membrane tension Adv. Biol. 2022 6 e2101020
Lipowsky, R. Remodeling of membrane shape and topology by curvature elasticity and membrane tension. Adv. Biol. 6, e2101020 (2022).
25. Yang ST Kreutzberger AJB Lee J Kiessling V Tamm LK The role of cholesterol in membrane fusion Chem. Phys. Lipids 2016 199 136 143 27179407
Yang, S. T., Kreutzberger, A. J. B., Lee, J., Kiessling, V. & Tamm, L. K. The role of cholesterol in membrane fusion. Chem. Phys. Lipids 199, 136–143 (2016).27179407
26. Zhang Z Jackson MB Membrane bending energy and fusion pore kinetics in Ca(2+)-triggered exocytosis Biophys. J. 2010 98 2524 2534 20513396
Zhang, Z. & Jackson, M. B. Membrane bending energy and fusion pore kinetics in Ca(2+)-triggered exocytosis. Biophys. J. 98, 2524–2534 (2010).20513396
27. Martens S Kozlov MM McMahon HT How synaptotagmin promotes membrane fusion Science 2007 316 1205 1208 17478680
Martens, S., Kozlov, M. M. & McMahon, H. T. How synaptotagmin promotes membrane fusion. Science 316, 1205–1208 (2007).17478680
28. Hui E Johnson CP Yao J Dunning FM Chapman ER Synaptotagmin-mediated bending of the target membrane is a critical step in Ca(2+)-regulated fusion Cell 2009 138 709 721 19703397
Hui, E., Johnson, C. P., Yao, J., Dunning, F. M. & Chapman, E. R. Synaptotagmin-mediated bending of the target membrane is a critical step in Ca(2+)-regulated fusion. Cell 138, 709–721 (2009).19703397
29. Herrick DZ Sterbling S Rasch KA Hinderliter A Cafiso DS Position of synaptotagmin I at the membrane interface: cooperative interactions of tandem C2 domains Biochemistry 2006 45 9668 9674 16893168
Herrick, D. Z., Sterbling, S., Rasch, K. A., Hinderliter, A. & Cafiso, D. S. Position of synaptotagmin I at the membrane interface: cooperative interactions of tandem C2 domains. Biochemistry 45, 9668–9674 (2006).16893168
30. Ali Moussa HY Park Y Electrostatic regulation of the cis- and trans-membrane interactions of synaptotagmin-1 Sci. Rep. 2022 12 22407 36575295
Ali Moussa, H. Y. & Park, Y. Electrostatic regulation of the cis- and trans-membrane interactions of synaptotagmin-1. Sci. Rep. 12, 22407 (2022).36575295
31. McMahon HT Kozlov MM Martens S Membrane curvature in synaptic vesicle fusion and beyond Cell 2010 140 601 605 20211126
McMahon, H. T., Kozlov, M. M. & Martens, S. Membrane curvature in synaptic vesicle fusion and beyond. Cell 140, 601–605 (2010).20211126
32. Sudhof TC Calcium control of neurotransmitter release Cold Spring Harb. Perspect. Biol. 2012 4 a011353 22068972
Sudhof, T. C. Calcium control of neurotransmitter release. Cold Spring Harb. Perspect. Biol. 4, a011353 (2012).22068972
33. Melland H Arvell EH Gordon SL Disorders of synaptic vesicle fusion machinery J. Neurochem. 2021 157 130 164 32916768
Melland, H., Arvell, E. H. & Gordon, S. L. Disorders of synaptic vesicle fusion machinery. J. Neurochem. 157, 130–164 (2021).32916768
34. Chernomordik L Kozlov MM Zimmerberg J Lipids in biological membrane fusion J. Membr. Biol. 1995 146 1 14 7563032
Chernomordik, L., Kozlov, M. M. & Zimmerberg, J. Lipids in biological membrane fusion. J. Membr. Biol. 146, 1–14 (1995).7563032
35. Chen Z Rand RP The influence of cholesterol on phospholipid membrane curvature and bending elasticity Biophys. J. 1997 73 267 276 9199791
Chen, Z. & Rand, R. P. The influence of cholesterol on phospholipid membrane curvature and bending elasticity. Biophys. J. 73, 267–276 (1997).9199791
36. Ivankin A Kuzmenko I Gidalevitz D Cholesterol mediates membrane curvature during fusion events Phys. Rev. Lett. 2012 108 238103 23003994
Ivankin, A., Kuzmenko, I. & Gidalevitz, D. Cholesterol mediates membrane curvature during fusion events. Phys. Rev. Lett. 108, 238103 (2012).23003994
37. Kreutzberger AJ Kiessling V Tamm LK High cholesterol obviates a prolonged hemifusion intermediate in fast SNARE-mediated membrane fusion Biophys. J. 2015 109 319 329 26200867
Kreutzberger, A. J., Kiessling, V. & Tamm, L. K. High cholesterol obviates a prolonged hemifusion intermediate in fast SNARE-mediated membrane fusion. Biophys. J. 109, 319–329 (2015).26200867
38. Wu L Courtney KC Chapman ER Cholesterol stabilizes recombinant exocytic fusion pores by altering membrane bending rigidity Biophys. J. 2021 120 1367 1377 33582136
Wu, L., Courtney, K. C. & Chapman, E. R. Cholesterol stabilizes recombinant exocytic fusion pores by altering membrane bending rigidity. Biophys. J. 120, 1367–1377 (2021).33582136
39. Jahn R Scheller RH SNAREs-engines for membrane fusion Nat. Rev. Mol. Cell Biol. 2006 7 631 643 16912714
Jahn, R. & Scheller, R. H. SNAREs-engines for membrane fusion. Nat. Rev. Mol. Cell Biol. 7, 631–643 (2006).16912714
40. Brunger AT Choi UB Lai Y Leitz J Zhou Q Molecular mechanisms of fast neurotransmitter release Annu Rev. Biophys. 2018 47 469 497 29792815
Brunger, A. T., Choi, U. B., Lai, Y., Leitz, J. & Zhou, Q. Molecular mechanisms of fast neurotransmitter release. Annu Rev. Biophys. 47, 469–497 (2018).29792815
41. Laude AJ Prior IA Plasma membrane microdomains: organization, function and trafficking Mol. Membr. Biol. 2004 21 193 205 15204627
Laude, A. J. & Prior, I. A. Plasma membrane microdomains: organization, function and trafficking. Mol. Membr. Biol. 21, 193–205 (2004).15204627
42. Willmann R Cholesterol and lipid microdomains stabilize the postsynapse at the neuromuscular junction EMBO J. 2006 25 4050 4060 16932745
Willmann, R. et al. Cholesterol and lipid microdomains stabilize the postsynapse at the neuromuscular junction. EMBO J. 25, 4050–4060 (2006).16932745
43. Korade Z Kenworthy AK Lipid rafts, cholesterol, and the brain Neuropharmacology 2008 55 1265 1273 18402986
Korade, Z. & Kenworthy, A. K. Lipid rafts, cholesterol, and the brain. Neuropharmacology 55, 1265–1273 (2008).18402986
44. Murray DH Tamm LK Clustering of syntaxin-1A in model membranes is modulated by phosphatidylinositol 4,5-bisphosphate and cholesterol Biochemistry 2009 48 4617 4625 19364135
Murray, D. H. & Tamm, L. K. Clustering of syntaxin-1A in model membranes is modulated by phosphatidylinositol 4,5-bisphosphate and cholesterol. Biochemistry 48, 4617–4625 (2009).19364135
45. Sieber JJ Anatomy and dynamics of a supramolecular membrane protein cluster Science 2007 317 1072 1076 17717182
Sieber, J. J. et al. Anatomy and dynamics of a supramolecular membrane protein cluster. Science 317, 1072–1076 (2007).17717182
46. Feringa FM van der Kant R Cholesterol and Alzheimer’s disease; from risk genes to pathological effects Front. Aging Neurosci. 2021 13 690372 34248607
Feringa, F. M. & van der Kant, R. Cholesterol and Alzheimer’s disease; from risk genes to pathological effects. Front. Aging Neurosci. 13, 690372 (2021).34248607
47. Hampel H The amyloid-beta pathway in Alzheimer’s disease Mol. Psychiatry 2021 26 5481 5503 34456336
Hampel, H. et al. The amyloid-beta pathway in Alzheimer’s disease. Mol. Psychiatry 26, 5481–5503 (2021).34456336
48. Jack CR Jr 11 C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment Brain 2008 131 665 680 18263627
Jack, C. R. Jr et al. 11 C PiB and structural MRI provide complementary information in imaging of Alzheimer’s disease and amnestic mild cognitive impairment. Brain 131, 665–680 (2008).18263627
49. Zhao J Liu X Xia W Zhang Y Wang C Targeting amyloidogenic processing of APP in Alzheimer’s disease Front. Mol. Neurosci. 2020 13 137 32848600
Zhao, J., Liu, X., Xia, W., Zhang, Y. & Wang, C. Targeting amyloidogenic processing of APP in Alzheimer’s disease. Front. Mol. Neurosci. 13, 137 (2020).32848600
50. Capitini C APP and Bace1: differential effect of cholesterol enrichment on processing and plasma membrane mobility iScience 2023 26 106611 37128606
Capitini, C. et al. APP and Bace1: differential effect of cholesterol enrichment on processing and plasma membrane mobility. iScience 26, 106611 (2023).37128606
51. Cordy JM Hussain I Dingwall C Hooper NM Turner AJ Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein Proc. Natl Acad. Sci. USA 2003 100 11735 11740 14504402
Cordy, J. M., Hussain, I., Dingwall, C., Hooper, N. M. & Turner, A. J. Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proc. Natl Acad. Sci. USA 100, 11735–11740 (2003).14504402
52. Wang, H. et al. Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol. Proc. Natl Acad. Sci. USA10.1073/pnas.2102191118 (2021).
53. Stewart KL Radford SE Amyloid plaques beyond Abeta: a survey of the diverse modulators of amyloid aggregation Biophys. Rev. 2017 9 405 419 28631243
Stewart, K. L. & Radford, S. E. Amyloid plaques beyond Abeta: a survey of the diverse modulators of amyloid aggregation. Biophys. Rev. 9, 405–419 (2017).28631243
54. Gellermann GP Appel TR Davies P Diekmann S Paired helical filaments contain small amounts of cholesterol, phosphatidylcholine and sphingolipids Biol. Chem. 2006 387 1267 1274 16972796
Gellermann, G. P., Appel, T. R., Davies, P. & Diekmann, S. Paired helical filaments contain small amounts of cholesterol, phosphatidylcholine and sphingolipids. Biol. Chem. 387, 1267–1274 (2006).16972796
55. Zhou X Xu J Free cholesterol induces higher beta-sheet content in Abeta peptide oligomers by aromatic interaction with Phe19 PLoS ONE 2012 7 e46245 23049991
Zhou, X. & Xu, J. Free cholesterol induces higher beta-sheet content in Abeta peptide oligomers by aromatic interaction with Phe19. PLoS ONE 7, e46245 (2012).23049991
56. Fernandez-Perez EJ Effect of cholesterol on membrane fluidity and association of abeta oligomers and subsequent neuronal damage: a double-edged sword Front. Aging Neurosci. 2018 10 226 30123122
Fernandez-Perez, E. J. et al. Effect of cholesterol on membrane fluidity and association of abeta oligomers and subsequent neuronal damage: a double-edged sword. Front. Aging Neurosci. 10, 226 (2018).30123122
57. Rudajev V Novotny J Cholesterol as a key player in amyloid beta-mediated toxicity in Alzheimer’s disease Front. Mol. Neurosci. 2022 15 937056 36090253
Rudajev, V. & Novotny, J. Cholesterol as a key player in amyloid beta-mediated toxicity in Alzheimer’s disease. Front. Mol. Neurosci. 15, 937056 (2022).36090253
58. Habchi J Cholesterol catalyses Abeta42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes Nat. Chem. 2018 10 673 683 29736006
Habchi, J. et al. Cholesterol catalyses Abeta42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes. Nat. Chem. 10, 673–683 (2018).29736006
59. Michaels TCT Dynamics of oligomer populations formed during the aggregation of Alzheimer’s Abeta42 peptide Nat. Chem. 2020 12 445 451 32284577
Michaels, T. C. T. et al. Dynamics of oligomer populations formed during the aggregation of Alzheimer’s Abeta42 peptide. Nat. Chem. 12, 445–451 (2020).32284577
60. Terakawa MS Impact of membrane curvature on amyloid aggregation Biochim. Biophys. Acta Biomembr. 2018 1860 1741 1764 29709613
Terakawa, M. S. et al. Impact of membrane curvature on amyloid aggregation. Biochim. Biophys. Acta Biomembr. 1860, 1741–1764 (2018).29709613
61. Sugiura Y Ikeda K Nakano M High membrane curvature enhances binding, conformational changes, and fibrillation of amyloid-beta on lipid bilayer surfaces Langmuir 2015 31 11549 11557 26474149
Sugiura, Y., Ikeda, K. & Nakano, M. High membrane curvature enhances binding, conformational changes, and fibrillation of amyloid-beta on lipid bilayer surfaces. Langmuir 31, 11549–11557 (2015).26474149
62. Tahirbegi B A novel abeta(40) assembly at physiological concentration Sci. Rep. 2020 10 9477 32528074
Tahirbegi, B. et al. A novel abeta(40) assembly at physiological concentration. Sci. Rep. 10, 9477 (2020).32528074
63. Fabiani C Antollini SS Alzheimer’s disease as a membrane disorder: spatial cross-talk among beta-amyloid peptides, nicotinic acetylcholine receptors and lipid rafts Front. Cell. Neurosci. 2019 13 309 31379503
Fabiani, C. & Antollini, S. S. Alzheimer’s disease as a membrane disorder: spatial cross-talk among beta-amyloid peptides, nicotinic acetylcholine receptors and lipid rafts. Front. Cell. Neurosci. 13, 309 (2019).31379503
64. Sahoo A Matysiak S Effects of applied surface-tension on membrane-assisted Abeta aggregation Phys. Chem. Chem. Phys. 2021 23 20627 20633 34514475
Sahoo, A. & Matysiak, S. Effects of applied surface-tension on membrane-assisted Abeta aggregation. Phys. Chem. Chem. Phys. 23, 20627–20633 (2021).34514475
65. Hernandez F Tau aggregation Neuroscience 2023 518 64 69 35525497
Hernandez, F. et al. Tau aggregation. Neuroscience 518, 64–69 (2023).35525497
66. Thijssen EH Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer’s disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study Lancet Neurol. 2021 20 739 752 34418401
Thijssen, E. H. et al. Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer’s disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study. Lancet Neurol. 20, 739–752 (2021).34418401
67. Wray S Noble W Linking amyloid and tau pathology in Alzheimer’s disease: the role of membrane cholesterol in Abeta-mediated tau toxicity J. Neurosci. 2009 29 9665 9667 19657019
Wray, S. & Noble, W. Linking amyloid and tau pathology in Alzheimer’s disease: the role of membrane cholesterol in Abeta-mediated tau toxicity. J. Neurosci. 29, 9665–9667 (2009).19657019
68. Bok E Role of the lipid membrane and membrane proteins in tau pathology Front. Cell Dev. Biol. 2021 9 653815 33996814
Bok, E. et al. Role of the lipid membrane and membrane proteins in tau pathology. Front. Cell Dev. Biol. 9, 653815 (2021).33996814
69. Sallaberry CA Tau and membranes: interactions that promote folding and condensation Front. Cell Dev. Biol. 2021 9 725241 34621743
Sallaberry, C. A. et al. Tau and membranes: interactions that promote folding and condensation. Front. Cell Dev. Biol. 9, 725241 (2021).34621743
70. Goux WJ Rodriguez S Sparkman DR Analysis of the core components of Alzheimer paired helical filaments. A gas chromatography/mass spectrometry characterization of fatty acids, carbohydrates and long-chain bases FEBS Lett. 1995 366 81 85 7789523
Goux, W. J., Rodriguez, S. & Sparkman, D. R. Analysis of the core components of Alzheimer paired helical filaments. A gas chromatography/mass spectrometry characterization of fatty acids, carbohydrates and long-chain bases. FEBS Lett. 366, 81–85 (1995).7789523
71. Tuck BJ Cholesterol determines the cytosolic entry and seeded aggregation of tau Cell Rep. 2022 39 110776 35508140
Tuck, B. J. et al. Cholesterol determines the cytosolic entry and seeded aggregation of tau. Cell Rep. 39, 110776 (2022).35508140
72. El Mammeri N Gampp O Duan P Hong M Membrane-induced tau amyloid fibrils Commun. Biol. 2023 6 467 37117483
El Mammeri, N., Gampp, O., Duan, P. & Hong, M. Membrane-induced tau amyloid fibrils. Commun. Biol. 6, 467 (2023).37117483
73. Mahul-Mellier AL The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is one of the major drivers of neurodegeneration Proc. Natl Acad. Sci. USA 2020 117 4971 4982 32075919
Mahul-Mellier, A. L. et al. The process of Lewy body formation, rather than simply alpha-synuclein fibrillization, is one of the major drivers of neurodegeneration. Proc. Natl Acad. Sci. USA 117, 4971–4982 (2020).32075919
74. Galvagnion C Lipid vesicles trigger alpha-synuclein aggregation by stimulating primary nucleation Nat. Chem. Biol. 2015 11 229 234 25643172
Galvagnion, C. et al. Lipid vesicles trigger alpha-synuclein aggregation by stimulating primary nucleation. Nat. Chem. Biol. 11, 229–234 (2015).25643172
75. den Jager WA Sphingomyelin in Lewy inclusion bodies in Parkinson’s disease Arch. Neurol. 1969 21 615 619 4187718
den Jager, W. A. Sphingomyelin in Lewy inclusion bodies in Parkinson’s disease. Arch. Neurol. 21, 615–619 (1969).4187718
76. Bosco DA Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization Nat. Chem. Biol. 2006 2 249 253 16565714
Bosco, D. A. et al. Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization. Nat. Chem. Biol. 2, 249–253 (2006).16565714
77. Jakubec M Cholesterol-containing lipid nanodiscs promote an alpha-synuclein binding mode that accelerates oligomerization FEBS J. 2021 288 1887 1905 32892498
Jakubec, M. et al. Cholesterol-containing lipid nanodiscs promote an alpha-synuclein binding mode that accelerates oligomerization. FEBS J. 288, 1887–1905 (2021).32892498
78. Qi Z Wan M Zhang J Li Z Influence of cholesterol on the membrane binding and conformation of alpha-synuclein J. Phys. Chem. B 2023 127 1956 1964 36812386
Qi, Z., Wan, M., Zhang, J. & Li, Z. Influence of cholesterol on the membrane binding and conformation of alpha-synuclein. J. Phys. Chem. B 127, 1956–1964 (2023).36812386
79. Husain MA Laurent B Plourde M APOE and Alzheimer’s disease: from lipid transport to physiopathology and therapeutics Front. Neurosci. 2021 15 630502 33679311
Husain, M. A., Laurent, B. & Plourde, M. APOE and Alzheimer’s disease: from lipid transport to physiopathology and therapeutics. Front. Neurosci. 15, 630502 (2021).33679311
80. Marais AD Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease Pathology 2019 51 165 176 30598326
Marais, A. D. Apolipoprotein E in lipoprotein metabolism, health and cardiovascular disease. Pathology 51, 165–176 (2019).30598326
81. Huang YA Zhou B Wernig M Sudhof TC ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and abeta secretion Cell 2017 168 427 441.e421 28111074
Huang, Y. A., Zhou, B., Wernig, M. & Sudhof, T. C. ApoE2, ApoE3, and ApoE4 differentially stimulate APP transcription and abeta secretion. Cell 168, 427–441.e421 (2017).28111074
82. Di Battista AM Heinsinger NM Rebeck GW Alzheimer’s disease genetic risk factor APOE-epsilon4 also affects normal brain function Curr. Alzheimer Res. 2016 13 1200 1207 27033053
Di Battista, A. M., Heinsinger, N. M. & Rebeck, G. W. Alzheimer’s disease genetic risk factor APOE-epsilon4 also affects normal brain function. Curr. Alzheimer Res. 13, 1200–1207 (2016).27033053
83. Raulin AC ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies Mol. Neurodegener. 2022 17 72 36348357
Raulin, A. C. et al. ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Mol. Neurodegener. 17, 72 (2022).36348357
84. Dugger, B. N. & Dickson, D. W. Pathology of neurodegenerative diseases. Cold Spring Harb. Perspect. Biol.10.1101/cshperspect.a028035 (2017).
85. Kacher R Mounier C Caboche J Betuing S Altered cholesterol homeostasis in Huntington’s disease Front Aging Neurosci. 2022 14 797220 35517051
Kacher, R., Mounier, C., Caboche, J. & Betuing, S. Altered cholesterol homeostasis in Huntington’s disease. Front Aging Neurosci. 14, 797220 (2022).35517051
86. Gao X Cholesterol modifies huntingtin binding to, disruption of, and aggregation on lipid membranes Biochemistry 2016 55 92 102 26652744
Gao, X. et al. Cholesterol modifies huntingtin binding to, disruption of, and aggregation on lipid membranes. Biochemistry 55, 92–102 (2016).26652744
87. Stonebraker AR Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation Protein Sci. 2023 32 e4642 37052951
Stonebraker, A. R. et al. Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation. Protein Sci. 32, e4642 (2023).37052951
88. Pineda-Torra I Siddique S Waddington KE Farrell R Jury EC Disrupted lipid metabolism in multiple sclerosis: a role for liver X receptors? Front. Endocrinol. 2021 12 639757
Pineda-Torra, I., Siddique, S., Waddington, K. E., Farrell, R. & Jury, E. C. Disrupted lipid metabolism in multiple sclerosis: a role for liver X receptors? Front. Endocrinol. 12, 639757 (2021).
