Brain Lipids in Synaptic Function and Neurological Disease

Clues to Innovative Therapeutic Strategies for Brain Disorders

1st Edition - May 12, 2015
Authors: Jacques Fantini, Nouara Yahi
Language: English
Hardback ISBN:
9 7 8 - 0 - 1 2 - 8 0 0 1 1 1 - 0
eBook ISBN:
9 7 8 - 0 - 1 2 - 8 0 0 4 9 2 - 0

Lipids are the most abundant organic compounds found in the brain, accounting for up to 50% of its dry weight. The brain lipidome includes several thousands of distinct bi… Read more

Brain Lipids in Synaptic Function and Neurological Disease

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Lipids are the most abundant organic compounds found in the brain, accounting for up to 50% of its dry weight. The brain lipidome includes several thousands of distinct biochemical structures whose expression may greatly vary according to age, gender, brain region, cell type, as well as subcellular localization. In synaptic membranes, brain lipids specifically interact with neurotransmitter receptors and control their activity. Moreover, brain lipids play a key role in the generation and neurotoxicity of amyloidogenic proteins involved in the pathophysiology of neurological diseases. The aim of this book is to provide for the first time a comprehensive overview of brain lipid structures, and to explain the roles of these lipids in synaptic function, and in neurodegenerative diseases, including Alzheimer’s, Creutzfeldt-Jakob’s and Parkinson’s. To conclude the book, the authors present new ideas that can drive innovative therapeutic strategies based on the knowledge of the role of lipids in brain disorders.

Dedication
About the Authors
Preface
Acknowledgments
Chapter 1: Chemical Basis of Lipid Biochemistry
- Abstract
- 1.1. Introduction
- 1.2. Chemistry background
- 1.3. Molecular interactions
- 1.4. Solubility in water: what is it?
- 1.5. Lipid biochemistry
- 1.6. Biochemical diversity of brain lipids
- 1.7. A key experiment: lipid analysis by thin layer chromatography
Chapter 2: Brain Membranes
- Abstract
- 2.1. Why lipids are different from all other biomolecules
- 2.2. Role of structured water in molecular interactions
- 2.3. Lipid self-assembly, a water-driven process?
- 2.4. Lipid–lipid interactions: why such a high specificity?
- 2.5. Nonbilayer phases and lipid dynamics
- 2.6. The plasma membrane of glial cells and neurons: the lipid perspective
- 2.7. Key experiments on lipid density
Chapter 3: Lipid Metabolism and Oxidation in Neurons and Glial Cells
- Abstract
- 3.1. General aspects of lipid metabolism
- 3.2. Cholesterol
- 3.3. Sphingolipids
- 3.4. Phosphoinositides
- 3.5. Phosphatidic acid
- 3.6. Endocannabinoids
- 3.7. Lipid peroxidation
- 3.8. Key experiment: Alzheimer’s disease, cholesterol, and statins: where is the link?
Chapter 4: Variations of Brain Lipid Content
- Abstract
- 4.1. Brain lipids: how to bring order to the galaxy
- 4.2. Variations in brain cholesterol content
- 4.3. Variations in brain ganglioside content
- 4.4. Variations in myelin lipids
- 4.5. Impact of nutrition on brain lipid content
- 4.6. Key experiment: the GM1/GM3 balance and Alzheimer’s disease
Chapter 5: A Molecular View of the Synapse
- Abstract
- 5.1. The synapse: a tripartite entity?
- 5.2. Role of gangliosides in glutamate clearance
- 5.3. Neurotransmitters and their receptors: what physicochemical properties reveal
- 5.4. A dual receptor model for serotonin
- 5.5. A dual receptor model for anandamide
- 5.6. Control of synaptic functions by gangliosides
- 5.7. Control of synaptic functions by cholesterol
- 5.8. Key experiments: debunking myths in neurosciences
Chapter 6: Protein–Lipid Interactions in the Brain
- Abstract
- 6.1. General aspects of protein–lipid interactions
- 6.2. Annular versus nonannular lipids
- 6.3. Interactions between membrane lipids and cytoplasmic domains
- 6.4. Interactions between membrane lipids and transmembrane domains
- 6.5. Interactions between membrane lipids and extracellular domains
- 6.6. Chaperone effects
- 6.7. Conclusions
- 6.8. Key experiment: the Langmuir monolayer as a universal tool for the study of lipid–protein interactions
Chapter 7: Lipid Regulation of Receptor Function
- Abstract
- 7.1. Specific lipid requirement of membrane proteins
- 7.2. Nicotinic acetylcholine receptor
- 7.3. Cholesterol- and ganglioside-binding domains in serotonin receptors
- 7.4. Cholesterol- and GalCer-binding domains in sigma-1 receptors
- 7.5. GM1-binding domain in high-affinity NGF receptor
- 7.6. Phosphoinositide binding to purinergic receptors
- 7.7. Key experiment: transfection of membrane receptors: what about lipids?
Chapter 8: Common Mechanisms in Neurodegenerative Diseases
- Abstract
- 8.1. Amyloidosis: a brief history
- 8.2. Protein structure
- 8.3. Protein folding
- 8.4. Intrinsically disordered proteins (IDPs): the dark side of the proteome
- 8.5. Lipid rafts as platforms for amyloid landing and conversions
- 8.6. Amyloid pores
- 8.7. Amyloid fibrils
- 8.8. Common molecular mechanisms of oligomerization and aggregation
- 8.9. Therapeutic strategies based on lipid rafts
- 8.10. A key experiment: common structure of amyloid oligomers implies common mechanism of pathogenesis
Chapter 9: Creutzfeldt–Jakob Disease
- Abstract
- 9.1. Prion diseases
- 9.2. PrP: structural features, biological functions, and role in neurological diseases
- 9.3. The mechanism or prion replication: a great intuition and an intellectual journey of an imperturbable logic
- 9.4. Role of lipid rafts in the conformational plasticity of PrP
- 9.5. Conclusion of the investigation: who is guilty, who is innocent?
- 9.6. Key experiment: adenine is a minimal aromatic compound that self-aggregates in water through π–π stacking interactions
Chapter 10: Parkinson’s Disease
- Abstract
- 10.1. Parkinson’s disease and synucleopathies
- 10.2. α-Synuclein
- 10.3. Intracellular α-synuclein binds to synaptic vesicles and regulates vesicle trafficking, docking, and recycling
- 10.4. α-Synuclein is secreted, extracellular, and taken up by several brain cell types
- 10.5. α-Synuclein: a multifaceted protein with exceptional conformational plasticity
- 10.6. How α-synuclein interacts with membrane lipids
- 10.7. Oligomerization of α-synuclein into Ca²⁺-permeable annular channels
- 10.8. Electrophysiological studies of oligomeric α-synuclein channels
- 10.9. Cellular targets for α-synuclein in the brain: the lipid connection
- 10.10. Conclusion of the investigation: who is guilty, who is innocent?
- 10.11. Key experiment: pesticides and animal models of Parkinson’s disease
Chapter 11: Alzheimer’s Disease
- Abstract
- 11.1. Alzheimer’s disease: a rapid survey, from 1906 to 2014
- 11.2. The amyloid paradigm
- 11.3. The calcium hypothesis of Alzheimer’s disease
- 11.4. Amyloid pores: β, α, or both?
- 11.5. Cholesterol
- 11.6. GM1
- 11.7. Lipid rafts: matrix for APP processing and factory for Aβ production
- 11.8. Gender-specific mechanisms
- 11.9. Conclusions of the inquiry
- 11.10. Key experiment: a blood-based test to predict Alzheimer’s disease?
Chapter 12: Viral and Bacterial Diseases
- Abstract
- 12.1. Overview of brain pathogens
- 12.2. Pathogen traffic to the brain
- 12.3. Overview of brain pathogens
- 12.4. Key experiment: what is a virus receptor?
Chapter 13: A Unifying Theory
- Abstract
- 13.1. Why do we need a unifying theory?
- 13.2. Bacteria, viruses, and amyloids converge at brain membranes
- 13.3. Glycosphingolipids and cholesterol in brain membranes: “un pas de deux”
- 13.4. Geometric aspects of glycolipid–protein and cholesterol interactions
- 13.5. Why two lipid receptors are better than one?
- 13.6. When cholesterol plays two roles
- 13.7. Structural disorder as a common trait of pathogenicity
- 13.8. Key experiment: probes to study cholesterol and/or glycolipid-dependent mechanisms
Chapter 14: Therapeutic Strategies for Neurodegenerative Diseases
- Abstract
- 14.1. Proteins involved in brain diseases considered as infectious proteins
- 14.2. How to prevent the interaction of pathogenic proteins with brain membranes
- 14.3. How to prevent the insertion of pathogenic proteins into brain membranes
- 14.4. How to block amyloid pore formation
- 14.5. A universal ganglioside-binding peptide
- 14.6. A universal squatter of cholesterol-binding sites
- 14.7. Could anti-HIV drugs also be considered for the treatment of neurodegenerative diseases?
- 14.8. Conclusions
- 14.9. A key experiment: PAMPA-BBB, a lipid-based model for the blood–brain barrier
Glossary
Subject Index

Jacques Fantini

Jacques Fantini was born in France in 1960. He has over 30 years of teaching and research experience in biochemistry and neurochemistry areas. Since 1998, he is professor of biochemistry and honorary member of the ‘Institut Universitaire de France’. He has demonstrated the implication of glycolipids in the attachment and fusion of HIV-1 with the plasma membrane of target cells, and has published several important articles in this field. He is an active member of the research group ‘Molecular Interactions in Model and Biological Membrane Systems’ led by Nouara Yahi. This group is internationally recognized for studies of lipid-lipid and lipid-protein interactions pertaining to virus fusion, amyloid aggregation, oligomerization and pore formation. Together with Nouara Yahi, Jacques Fantini has discovered the universal sphingolipid-binding domain (SBD) in proteins with no sequence homology but sharing common structural features mediating sphingolipid recognition. The SBD is present in a broad range of infectious and amyloid proteins, revealing common mechanisms of pathogenesis in viral and bacterial brain infections, and in neurodegenerative diseases. His current research is focused on the molecular organization of the synapse in physiological and pathological conditions. Jacques Fantini is the author/co-author of 175 articles (PubMed), with 7500 citations and a H-index of 49. He has also published 4 patent applications. Jacques Fantini personal web site: https://jfantini.jimdo.com

Affiliations and expertise

Molecular Interactions in Model and Biological Membranes Laboratory, Faculty of Science and Technology, Marseille, France

Nouara Yahi

Nouara Yahi was born in France in 1964. She has accumulated 25 years of fundamental research and teaching experience in virology and molecular biology areas. She has been a pioneer in the analysis of resistance mutations in patients with HIV infections, and has published several important articles in this field. She is currently professor of biochemistry at Aix-Marseille University and leader of the research group ‘Molecular Interactions in Model and Biological Membrane Systems’. This group is internationally recognized for studies of lipid-lipid and lipid-protein interactions pertaining to virus fusion, amyloid aggregation, oligomerization and pore formation. Together with her teammate Jacques Fantini, Nouara Yahi has discovered the universal sphingolipid-binding domain (SBD) in proteins with no sequence homology but sharing common structural features mediating sphingolipid recognition. The SBD is present in a broad range of infectious and amyloid proteins, revealing common mechanisms of pathogenesis in viral and bacterial brain infections, and in neurodegenerative diseases. Nouara Yahi is the author/co-author of 90 articles (PubMed), with 4400 citations and a H-index of 40. She has also published 5 patent applications.

Affiliations and expertise

Molecular Interactions in Model and Biological Membranes Laboratory, Faculty of Science and Technology, Marseille, France

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

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