Alzheimer's Disease: Recent Findings in Pathophysiology, Diagnostic and Therapeutic Modalities

Cover
Preface
Contents
Chapter 1 Alzheimer’s is a Multifactorial Disease
1.1 Introduction
1.2 Pathological Events
1.2.1 Amyloid Burden
1.2.2 Tau Toxicity
1.2.3 Metal Ion Toxicity
1.2.4 Oxidative Stress
1.2.5 Biomolecule Damage
1.2.6 Membrane Toxicity
1.2.7 Calcium Dyshomeostasis
1.2.8 Role of Cholesterol
1.2.9 Mitochondrial Dysfunction
1.2.10 Endoplasmic Reticulum Stress
1.2.11 Impairment in Telomerase Activity
1.2.12 Cholinergic Toxicity
1.2.13 Synaptic Dysfunction
1.2.14 Immune Outrage
1.2.15 Neurovascular Toxicity
1.2.16 Lymphatic Dysfunction
1.2.17 α-Synuclein Mediated Toxicity
1.2.18 Apoptosis Dysfunction
1.2.19 Aberrant Post-translational Modification
1.2.20 Microbiome Imbalance: Gut Bacterial Dysfunction
1.2.21 Glucose Hypometabolism
1.2.22 Insulin Resistance and Diabetes
1.2.23 Autophagy Dysfunction
1.2.24 Genetic Risk
1.3 Biomarkers and Diagnosis
1.4 Therapy
1.5 Conclusion
References
Chapter 2 The Genetic and Biochemical Basis of Alzheimer’s Disease
2.1 Alzheimer’s Disease: A Malady Rooted in Genetics and Pathophysiology
2.1.1 Hallmarks for AD
2.1.2 Genetics Controlling AD
2.2 Molecular Basis of AD: Seeing AD at the Level of Molecular Interactions
2.2.1 Formation of β-Amyloid Plaques
2.2.2 Decline in Neurotransmission
2.2.3 Tau Protein and Its Phosphorylation
2.2.4 Involvement of Oxidative Stress and Metabolism
2.2.5 Role of Calcium
2.2.6 Clinical Manifestation: Biochemical and Physiology Contribution
2.3 Amyloid Plaques: A Sticky Substance That Affects Brain Function
2.3.1 Neurofibrillary Tangles: Tau Turning Around Wrongly
2.3.2 When Amyloid Plaque Dysfunctions Together With Tau Pathology That Results in Havoc
2.3.3 Other Cellular Mishaps That Converge in the Anomaly of Homeostasis
2.4 Genetics as a Promising Tool for Alzheimer’s Disease
References
Chapter 3 Alzheimer’s Disease Pathology: A Tau Perspective
3.1 Tau and Alzheimer’s Disease
3.1.1 Alzheimer’s Disease
3.1.1.1 Tau Protein
3.1.1.2 Tau in AD Pathology
3.1.1.3 Tau Aggregation and Implications in AD
3.1.1.4 Tau in AD Diagnosis
3.1.1.5 Recent Advances in Tau-based Therapeutics
3.2 Conclusions
3.3 Future Perspectives for Small Molecules As Tau Therapeutics
References
Chapter 4 Structural Insights Into the Amyloidogenic Ab and Tau Species in Alzheimer’s disease Pathophysiology: Defining Functional Motifs
4.1 Introduction
4.1.1 Factors Influencing Amyloid Aggregation
4.2 Mechanistic Insight Into Amyloidogenesis: Defining the Intermediate Steps
4.3 Structural Correlation of Ab Pathological Aggregates in AD Etiology
4.3.1 Structural Elucidation of the Molecular Intermediates: Benefits of Using NMR
4.3.2 Probing the Ab Surface Interactions
4.3.3 Water Dynamics in Peptide Aggregation
4.3.4 NMR Derived Structural Models of Ab Fibrils
4.3.5 Role of the GxxxG Motif in Regulating the Aggregation and Neurotoxicity of Aβ
4.3.6 Role of Aβ-membrane Interactions in Prompting AD Pathophysiology
4.4 Tau Aggregation and Its Relevance in AD: Insights From NMR Spectroscopy
4.4.1 Molecular Events Underlying Tau Aggregation
4.4.2 Recent Structural Developments on Tau From NMR and Cryo-EM
4.4.3 Role of Liquid–Liquid Phase Separation in Amyloid Aggregation of Tau
4.5 Conclusion and Future Outlook
Acknowledgements
References
Chapter 5 Structural Insights on Aggregation Species of Aβ and Tau, and Their Implications in Alzheimer’s Disease
5.1 Amyloid Aggregation of Aβ and Tau in Alzheimer’s Disease
5.1.1 Different Amyloid Aggregation Species in Alzheimer’s Disease
5.1.2 Aggregation Species of Aβ and Their Pathological Relevance to AD
5.1.2.1 Aβ Oligomers
5.1.2.2 Aβ Fibrils
5.1.3 Aggregation Species of Tau and Their Pathological Relevance to AD
5.1.3.1 Tau Oligomers
5.1.3.2 Tau Fibrils
5.2 Atomic Structures of Tau and Aβ Fibrils
5.2.1 Atomic Structures of Tau Fibrils
5.2.1.1 Atomic Structures of Tau-derived Amyloid-forming Peptides by X-ray Crystallography
5.2.1.2 Atomic Structures of Tau Fibrils by Cryo-EM
5.2.1.3 Chemical Modifications Mediate the Structural Diversity of Tau Fibril Polymorphs
5.2.2 Atomic Structures of Aβ Fibrils
5.2.2.1 Aβ Fibril Structures Determined by ssNMR
5.2.2.2 Aβ Fibril Structures Determined by Cryo-EM
5.3 Fibril Polymorphism and Its Implication in AD
Abbreviations
Acknowledgements
References
Chapter 6 Aggregation Species of Amyloid-β and Tau Oligomers in Alzheimer’s Disease: Role in Therapeutics and Diagnostics
6.1 Introduction
6.2 Protein Aggregation Cascades and Various Species of Aggregates
6.3 Protein Aggregation Initiation and Underlying Mechanism
6.4 Propagation and Seeding Effect of Oligomeric Species
6.5 Isolation, Preparation and Characterization of Oligomeric Species
6.5.1 Amyloid-β (Aβ)
6.5.2 Tau
6.5.3 Co-oligomers
6.6 Pathological Aspects of Soluble Oligomers in AD
6.6.1 Neuron
6.6.2 Glia
6.7 Oligomers as Therapeutic Targets and Biomarkers
6.7.1 Therapeutic Targets
6.7.1.1 Small Molecules
6.7.1.2 Immunotherapy
6.7.2 Biomarkers
6.8 Conclusion
Abbreviations
Acknowledgements
References
Chapter 7 Role of Metal Ions in Alzheimer’s Disease: Mechanistic Aspects Contributing to Neurotoxicity
7.1 Introduction
7.1.1 The Amyloid Cascade Hypothesis
7.1.2 The Metal Hypothesis
7.1.3 Link Between the Two Hypotheses
7.1.4 Concluding Notes
7.2 Metal Ions, Aβ Peptides and Their Interactions
7.2.1 Cu(II)
7.2.2 Cu(I)
7.2.3 Zn(II)
7.2.4 Concluding Notes
7.3 Copper-mediated ROS Production
7.3.1 Redox Properties of Cu(Aβ) Species
7.3.2 Oxidative Damage
7.3.2.1 General Targets
7.3.2.2 Aβ Oxidative Damage
7.3.3 Influence on Aβ Self-assembly
7.4 Modulation of Aβ Self-assembly by Cu and Zn
7.4 Modulation of Ab Self-assembly by Cu and Zn
7.4.1 General Features
7.4.2 Mechanisms of Toxicity
7.4.3 Influence of the Aggregation State on the Cu(Aβ)induced ROS Production
7.4.4 Other Important Points to Consider
7.4.5 Future Lines of Research
7.5 Metal Targeting Compounds
7.6 Concluding Remarks
Abbreviations
Acknowledgements
References
Chapter 8 Microglial Blockade of the Amyloid Cascade: A New Therapeutic Frontier
8.1 Overview – Old and New Positions for Microglia in the Amyloid Cascade
8.2 Human Genetic Bases for AD Pathogenesis and Microglial Protection
8.2.1 Autosomal Dominant AD and Typical AD – Same Villain (Aβ), Different Origin Stories
8.2.2 Non-inflammatory Microglial Activation Lowers the Risk of AD
8.2.2.1 Microglial Activation Proteins – TREM2 and PLCγ2
8.2.2.2 Microglial Inhibition Proteins – PILRA, CD33, and INPP5D
8.2.3 Microglial Activation Defects Are a Typical AD Feature
8.3 Microglial TREM2 Activity Opposes the Amyloid Cascade
8.3.1 Microglial TREM2 and the Endo/Lysosomal System Oppose the Seeding of Amyloid Plaques
8.3.2 Microglial TREM2, ApoE, and TAM Receptors Attenuate amyloid Neurotoxicity Through Plaque Compaction
8.3.2.1 How Plaque Pathology Alters Microglia – The DAM Response
8.3.2.2 How Microglia Alter Plaque Pathology – A DAM Protective Barrier
8.3.3 AD-related Synapse Loss Is Independent of Trem2 and DAM Activation
8.3.4 TREM2 Restricts β-amyloid-facilitated Tau Pathogenesis
8.4 Therapeutic Strategies to Enhance Microglial Protection in AD
8.4.1 Augmenting the Activity of TREM2 and Its Downstream Effectors
8.4.2 Promoting Microglial Activity by Blocking ITIM/Checkpoint Proteins
8.4.3 Aducanumab Treatment May Confound Microglial Drug Responses
8.5 Concluding Remarks
Author Contributions
Acknowledgements
References
Chapter 9 Post-translational Modifications and Alzheimer’s Disease
9.1 Introduction
9.2 PTMs in AD
9.3 Protein Misfolding and Their Aggregation in AD Pathology
9.4 Phosphorylation
9.4.1 Phosphorylation of APP
9.4.2 Phosphorylation of BACE1
9.4.3 Phosphorylation of Tau
9.5 Glycosylation
9.5.1
Glycosylation of APP
9.5.2
Glycosylation of AD Related Proteins
9.5.3
and
Glycosylation of Tau
9.6 Ubiquitination
9.6.1 Ubiquitination of APP
9.6.2 Ubiquitination of BACE1
9.6.3 Ubiquitination of Tau
9.7 Sumoylation
9.7.1 Sumoylation of APP
9.7.2 Sumoylation of BACE1
9.7.3 Sumoylation of Tau
9.7.4 Sumoylation of HDAC1
9.8 Acetylation
9.8.1 Acetylation of BACE1
9.8.2 Acetylation of Tau
9.8.3 Acetylation of Histone
9.9 Acylation
9.9.1 Palmitoylation and N-myristoylation
9.9.2 Prenylation
9.10 S-Nitrosylation
9.11 Methylation
9.12 Solutions and Recommendations to Current Challenges
9.13 Conclusion and Future Trends
Abbreviations
References
Chapter 10 Autophagy: Role in Alzheimer’s Disease Pathophysiology and Therapeutic Avenues
10.1 Introduction
10.2 Alzheimer’s Disease: Etiological Hypothesis
10.3 Autophagy Dysfunction in Neurons During AD – Mechanisms Involved
10.3.1 Autophagy Initiation is Altered in AD – Defects in Autophagosome Formation, Elongation and Maturation
10.3.2 Impairment in Retrograde Transportation of Autophagosomes
10.3.3 Defects in Lysosomal Biogenesis
10.3.4 Defective Autophagosome–Lysosome Fusion and Lysosomal Proteolysis in AD
10.4 Autophagy in Glial Cells
10.5 Aβ Degradation and Autophagy
10.6 Cross-talk Between Apoptosis and Autophagy
10.7 Neuroinflammation and Autophagy
10.8 Targeting Autophagy for Therapeutic Strategies
10.8.1 Genetic Manipulation of Autophagy Regulators
10.8.2 Small Molecule Autophagy Inducers
10.8.2.1 mTOR Inhibitors
10.8.2.2 Enhancers of Autophagosome Synthesis
10.8.2.3 Enhancers of TFEB Activity – Targeting Lysosome Biogenesis
10.8.2.4 Promoters of Autophagosome Transport and Their Fusion with Lysosomes
10.8.2.5 Facilitators of Lysosomal Acidification and Digestion
10.9 Conclusion and Future Perspectives
List of Abbreviations
Conflict of Interest
Acknowledgements
References
Chapter 11 Transmission of Pathogenic Proteins and the Role of Microbial Infection in Alzheimer’s Disease Pathology
11.1 Introduction
11.2 AD Transmission
11.2.1 Cell-to-cell Transmission of Aβ and Tau
11.2.2 Transmission of Aβ and Tau Within the Brain
11.2.3 Human-to-human Transmission of AD Pathology
11.3 Role of Microbial Infection in Alzheimer’s Disease
11.3.1 Herpes Simplex Virus 1 (HSV 1) in AD
11.3.2 Human Herpes Virus (HHV) and Other Viruses
11.3.3 Role of Bacterial and Fungal Infection in AD
11.3.4 Microbial Role in the Gut–Brain Axis and AD
11.4 Conclusion and Future Outlook
References
Chapter 12 The Role of Gut Microbiome in Alzheimer’s Disease and Therapeutic Strategies
12.1 Introduction
12.2 Benefits of Gut Bacteria
12.3 Gut Microbiota and Brain Function
12.4 Gut Dysbiosis
12.4.1 Bacterial Amyloids, Inflammation, and Oxidative Stress
12.5 Therapy
12.5.1 Probiotic and Oligosaccharides Treatment
12.5.2 FMT Treatment
12.5.3 Small Molecule and Natural Product Treatment
12.6 Conclusion and Future Outlook
References
Chapter 13 Molecular Probes for the Diagnosis of Alzheimer’s Disease with Implications for Multiplexed and Multimodal Strategies
13.1 Introduction
13.2 Ab Biomarkers
13.2.1 Fluorescent Probes
13.2.1.1 Aβ Monomer
13.2.1.2 Aβ Oligomers (AβOs)
13.2.1.3 Aβ Plaques
13.2.2 Positron Emission Tomography (PET)
13.2.2.1 Antibody-based PET Probes for Ab
13.2.3 MRI Probes
13.2.4 Theranostic Probes: Drugs of the Future
13.3 Tau as a Biomarker
13.3.1 Fluorescent Probes
13.3.2 PET Probes for Tau
13.4 Neurodegeneration
13.5 Indirect Biomarkers
13.6 Challenges in AD Diagnosis
13.6.1 Meticulous Design and Targeting of Different Alloforms
13.6.2 Blood–Brain Barrier (BBB)
13.6.3 Circulating Biomarkers in Biofluids
13.7 Conclusion and Future Outlook
References
Chapter 14 Circulating Biomarkers for the Diagnosis of Alzheimer’s Disease
14.1 Introduction
14.1.1 Alzheimer’s Disease
14.1.2 Current Diagnosis and Limitations
14.1.3 Need for Circulating Biomarkers: Blood Biomarkers and Beyond
14.1.4 Classification of Circulating Biomarkers
14.2 Core AD Pathology Biomarkers in CSF and Blood
14.2.1 Ab Pathology Biomarkers
14.2.2 Tau Pathology Biomarkers
14.2.3 Inflammation Biomarkers
14.2.4 Synaptic Degeneration Biomarkers
14.2.5 Neuronal Injury Biomarkers
14.2.6 Vascular Injury Biomarkers
14.2.7
synuclein Pathology Biomarkers
14.2.8 TDP-43 Pathology Biomarkers
14.3 Associated Blood Biomarkers in AD Diagnosis
14.3.1 Associated Protein Biomarkers
14.3.2 Associated Metabolite Biomarkers
14.3.3 Circulating RNAs
14.4 Non-invasive Sources for Circulating Biomarkers – Saliva, Urine and Tears
14.4.1 Salivary Biomarkers
14.4.1.1 Ab Biomarkers
14.4.1.2 Tau Biomarkers
14.4.1.3 Lactoferrin
14.4.1.4 Acetylcholinesterase (AChE)
14.4.2 Urine Biomarkers
14.4.3 Tear Biomarkers
14.5 Challenges and Prospects for Circulating Biomarkers
14.6 Conclusion
References
Chapter 15 Lactoferrin: A Potential Theranostic Candidate for Alzheimer’s Disease
15.1 Introduction
15.2 Lactoferrin in AD
15.3 Lf: A Promising Circulatory Biomarker
15.4 Lf: A Multifunctional Therapeutic Candidate
15.5 Conclusion and Outlook
References
Chapter 16 Multifunctional Inhibitors of Multifaceted Ab Toxicity of Alzheimer’s Disease
16.1 Introduction
16.2 Targeting Individual Routes of Amyloid Pathology
16.2.1 Targeting Enzymatic Functions
16.2.2 Targeting Amyloid Aggregation
16.2.3 Targeting Membrane Toxicity
16.2.4 Targeting Metal Toxicity
16.2.5 Targeting Oxidative Stress
16.2.6 Targeting Mitochondrial Dysfunction
16.2.7 Targeting Neuroinflammation
16.3 Targeting Multiple Toxicities of AD Pathology
16.3.1 Small Molecule-based Multifunctional Inhibitors
16.3.2 Peptide-based Multifunctional Inhibitors
16.3.3 Polymeric Multifunctional Inhibitors
16.3.4 Natural Product-derived Multifunctional Inhibitors
16.4 Theranostic Probes
16.5 Conclusion and Future Directions
References
Chapter 17 Tau-targeting Therapeutic Strategies for Alzheimer’s Disease
17.1 Introduction
17.2 Strategies to Target Tau Pathology
17.3 Modulators of PTMs
17.3.1 Phosphatase Modulators
17.3.2 Kinase Inhibitors
17.3.2.1 GSK-3 and CDK5
17.3.2.2 CDK-5
17.3.2.3 c-Jun N-terminal kinases (JNK) and Other Kinases
17.3.3 Acetylation Modulators
17.4 Tau Aggregation Inhibitors
17.4.1 Small Molecule Inhibitors
17.4.2 Peptide Inhibitors
17.5 Microtubule Stabilizers
17.6 Immunotherapy
17.6.1 Active Immunotherapy
17.6.2 Passive Immunotherapy
17.7 Gene Therapy
17.8 Conclusions and Future Directions
Acknowledgements
References
Chapter 18 Computational Development of Alzheimer’s Therapeutics and Diagnostics
18.1 Introduction
18.2 AD Associated Drug Targets and Biomarkers
18.3 Molecular Mechanism of Amyloid Plaque Formation
18.4 Molecular Mechanism of the Formation of Paired Helical Filaments of Tau Protein
18.5 Computational Approaches for Developing Therapeutics and Diagnostics for AD
18.5.1 Molecular Docking, De Novo Design and Virtual Screening
18.5.2 Molecular Dynamics and Steered Molecular Dynamics
18.5.3 Binding Free Energy Calculations
18.5.4 Electronic Structure Theory Based Calculations
18.5.5 Machine Learning Approaches for Binding Affinity Prediction
18.6 Computational Design of Novel Therapeutics Against Drug Targets in AD
18.6.1 Design of Amyloid and Tau Busting Molecules
18.6.2 Design of Inhibitors for BACE1
18.6.3 Design of γ-Secretase Inhibitors
18.6.4 Design of Inhibitors for Acetylcholinesterase and Butyrylcholinesterase
18.6.5 Design of Inhibitors for Muscarinic and Nicotinic ACh Receptors (mAchR, nAchRs)
18.6.6 Design of Inhibitors for Monoamine Oxidases A and B
18.7 Computational Investigation of Off-target Binding of Diagnostic Agents
18.8 Design of Dual Targeting and Multifunctional Ligands
18.9 Design of PET Tracers for AD
18.10 Design of Optical Probes for Amyloid Imaging
18.11 Outlook and Conclusions
Acknowledgements
References
Chapter 19 Targeted Protein Degradation as a Therapeutic Avenue for Alzheimer’s Disease
19.1 Introduction
19.2 Targeted Protein Degradation (TPD)
19.2.1 Proteolysis Targeting Chimeras (PROTACs)
19.2.2 Photoswitchable PROTACs (PHOTACs)
19.2.3 Lysosome Targeting Chimeras (LYTACs)
19.3 Alzheimer’s Disease (AD)
19.3.1 Specific Knockdown of Endogenous Tau Protein
19.3.2 Amyloid Precursor Protein (APP) Processing
19.3.3 α-Secretase Cleavage Sites
19.3.4 Aβ Degrading Enzymes
19.3.5 Transcriptional Upregulation of ADAM10
19.3.6 Proteolytic Enzymes and Importance of Artificial Proteases
19.3.7 Metalloenzyme Mimic
19.4 Mimic of α-Secretase
19.5 Miniature Artificial Protease (mAP)
19.6 Conclusions and Future Directions
References
Chapter 20 Cell-based Therapy for Alzheimer’s Disease
20.1 Cell-based Therapy
20.1.1 Different Cell Sources for Cell Therapy and Their Categorization
20.2 Stem Cell Treatments for AD
References
Chapter 21 Experimental Models to Study Alzheimer’s Disease
21.1 In Vivo Models
21.1.1 Lipopolysaccharide (LPS) Induced Model
21.1.2 Streptozotocin Induced Model
21.1.3 Okadaic Acid Induced Model
21.1.4 Scopolamine Induced Memory Impairment
21.1.5 Amyloid Beta-peptide Induced Model
21.1.6 Transgenic Models
21.2 In Vitro AD Models
21.2.1 Induced Pluripotent Stem Cells (iPSCs) and a 3D Brain Organoid System
21.2.2 SH-SY5Y Cell Line
21.2.3 N2a Cells
21.2.4 Pheochromocytoma Cell Line (PC-12)
21.3 Conclusion
Acknowledgements
References
Chapter 22 Ethnic and Racial Differences in The Pathophysiology of Alzheimer’s Disease
22.1 Introduction
22.2 Cross-comparison of Racial and Ethnic Disparities Worldwide
22.2.1 North America
22.2.2 South America
22.2.3 Africa
22.2.4 Asia
22.2.5 Europe
22.2.6 Israel
22.3 Reasons for Ethnic and Racial Disparities
22.3.1 Genetic Factors
22.3.2 Cardiovascular and Cerebrovascular Disease and Other Comorbidities
22.3.3 Socioeconomic Factors
22.3.4 Cultural Differences
22.3.5 Immunity
22.4 Impact of Ethno-racial Aspects on Diagnostic Techniques
22.4.1 Impact of Cognitive Based Testing in AD
22.4.2 Impact of Neuro-imaging and Bio Fluids in AD
22.4.3 Impact of Electroencephalogram (Eeg) in Ethno-racial AD
22.5 Genetic Risk for Alzheimer’s Disease: Epidemiological Comparison
22.5.1 Apolipoprotein (APOE)
22.5.2 Sortilin-related Receptor 1 (SORL1)
22.5.3 Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)
22.5.4 Myeloid Cell Surface Antigen CD33 (CD33)
22.5.5 Myc Box-dependent-interacting Protein 1 (BIN1)
22.5.6 Phosphatidylinositol-binding Clathrin Assembly Protein (PICALM)
22.5.7 Clusterin (CLU)
22.5.8 A Few Other Genes
22.6 Non-genetic Risk for Alzheimer’s Disease: Epidemiological Comparison
22.6.1 Age
22.6.2 Gender
22.6.3 Family History
22.6.4 Cardiovascular Disease
22.6.5 Stroke
22.6.6 Hypertension
22.6.7 Diabetes
22.6.8 Lifestyle
22.7 Participation of Cohort Groups in Clinical Trials, Respective Outcomes and Medication
22.8 Neuropsychiatric Symptoms of AD in Ethno-racial Groups
22.9 Impact of Ethno-racial Factors in the Pathogenesis of Alzheimer’s Disease
22.10 Interferences to Lessen the Racial and Ethnic Disparities
22.10.1 Cultural Competence
22.10.2 Agencies and Grants
22.10.3 Outreach to Minorities
22.10.4 Screening Tool
22.11 Conclusion and Future Perspective
Acknowledgements
References
Subject Index