Alzheimer's Disease Research Guide

Animal Models for Understanding Mechanisms and Medications

1st Edition - July 25, 2024
Imprint: Academic Press
Author: Takaomi C. Saido
Language: English
Paperback ISBN:
9 7 8 - 0 - 4 4 3 - 2 8 9 7 9 - 8
eBook ISBN:
9 7 8 - 0 - 4 4 3 - 2 8 9 8 0 - 4

Alzheimer's Disease Research Guide: Animal Models for Understanding Mechanisms and Medications provides researchers with a comprehensive guide, detailing every aspect of Alzhei… Read more

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Alzheimer's Disease Research Guide: Animal Models for Understanding Mechanisms and Medications provides researchers with a comprehensive guide, detailing every aspect of Alzheimer's Disease research, including chapters on neuroinflammation, immunotherapy, biomarkers, and animal modeling. This book begins with historical perspectives of both pathological chronology and pathological biochemistry in relation to Alzheimer’s disease. Other chapters review Amyloidogenic AB and Non-Amyloidogenic tau and Metabolism of AB major components to the research and understanding of Alzheimer’s research. The book concludes with specific treatment chapters including how to develop safe, effective, and inexpensive medications and the application of genome editing to the treatment of Familial Alzheimer's Disease.

Written by world renowned expert in Alzheimer’s research, this book is a valuable resource for all researchers.

Cover image
Title page
Table of Contents
Copyright
Dedication
Preface
Advice for graduate students and postdocs
Advice for undergraduate and younger students
Advice for young principal investigators (PIs)
Advice for middle-aged PIs (in their early 40s before something happens)
Strategies for promotion of your laboratory members and international colleagues
Alzforum, PubMed, and BioRXiv
References
About the author
References
Abbreviations
Chapter 1 Introduction: Collaboration and competition together to maximize the velocity of research and development
Brief summary
References
Chapter 2 Pathological chronology and pathological biochemistry: The beginning of the beginning
Brief summary
1 Pathological chronology
2 Pathological biochemistry
References
Chapter 3 Human genetics: Establishment of cause-and-effect relationships
Brief summary
1 APP (FAD)
2 PSEN1 and PSEN2 (FAD)
3 MAPT (FTDP-17)
4 APOE4 (SAD risk factor)
References
Chapter 4 Two major culprits: Amyloidogenic Aβ and non-amyloidogenic tau
Brief summary
1 Aβ
2 Tau protein
References
Chapter 5 Exact relationship between Aβ40 and Aβ42: An overlooked discovery by Jungsu Kim and colleagues
Brief summary
1 A seeding hypothesis proposed by Peter Lansbury
2 Revolutionary discovery by Jungsu Kim and colleagues
References
Chapter 6 Metabolism of Aβ: Catabolic and glymphatic systems
Brief summary
1 Catabolic systems
2 Glymphatic systems
References
Chapter 7 Biology of time: The temporal distance between cause and effect
Brief summary
References
Chapter 8 First-generation animal models of Aβ amyoloidosis: Pros and cons of the overexpression paradigm
Brief summary
1 Generation of mutant APP- and APP/PS-overexpressing AD mouse models
2 Intrinsic pitfalls of mutant APP- and APP/PS-overexpressing mouse models
References
Chapter 9 Creation of single App knock-in mouse models and of single MAPT knock-in models: Demonstration of Aβ-tau axis
Brief summary
1 Creation of next-generation mouse models of Aβ amyloidosis
2 More questions about AD models
3 Animal models of frontotemporal dementia: Demonstration of an Aβ-tau axis
References
Chapter 10 Applications of App and MAPT knock-in mice to understanding disease mechanisms
Brief summary
1 Effect of Aβ pathology on entorhinal-hippocampal circuits responsible for spatial memory
2 Effect of Aβ pathology on pericyte-mediated capillary constriction
3 Myelin damage and Aβ pathology
4 Other findings
References
Chapter 11 Neuroinflammation: Microgliosis and astrocytosis in the days of microscopic omics
Brief summary
1 Neuroinflammation in AD
2 Application of spatial transcriptomics and in situsequencing
References
Chapter 12 Central and peripheral nervous system, immune systems and digestive system: AD as a systemic disorder
Brief summary
1 Immune systems
2 Digestive system
References
Chapter 13 Failure of more than 400 candidate medications in clinical trials before 2020
Brief summary
1 Conventional enzyme inhibitors
2 Substrate-selective secretase inhibitors: Hopes for the future
References
Chapter 14 Therapeutic antibodies as a Wright Brothers' airplane: Clinical proof-of-concept
Brief summary
1 Therapeutic antibodies before 2020
2 Lecanemab and donanemab: Therapeutic antibodies that have partially succeeded
References
Chapter 15 Biomarkers for presymptomatic diagnosis and prognosis
Brief summary
1 Visualization of Aβ amyloidosis and tau pathology by PET
2 CSF biomarkers
3 Blood/plasma biomarkers
4 Polygenic prediction of age of on-set
5 Other biomarkers
References
Chapter 16 Targeting somatostatin receptor heterodimer for effective and economically viable medications without side effects
Brief summary
References
Chapter 17 Application of genome editing to the treatment of familial AD
Brief summary
1 Prevention of AD pathology by genome editing
2 Experimental search for protective mutation(s)
References
Chapter 18 Identifying significant and insignificant publications: Prelude for Chapter 19
Brief summary
References
Chapter 19 Journal of Negative Data for the days of generative AI-assisted publication
Brief summary
References
Chapter 20 Conclusions: Let's make the world ADless!
Brief summary
References
Eulogy to the late Yasuo Ihara
Postscript
Acknowledgments
Conflicts of interest
References
Index

Takaomi C. Saido

Takaomi C. Saido is a graduate of Tsukuba University, Japan, where he majored in biophysics, and was subsequently trained in the Graduate School of Pharmaceutical Science, the University of Tokyo where he obtained PhD. During the graduate school years, he spent a year as a Visiting Scholar in the Department of Engineering and Applied Physics, Cornell University, NY. In the beginning of his career at the Tokyo Metropolitan Institute of Medical Science as a Research Scientist, he focused on proteolytic reactions conducted by calpain, a cytosolic calcium-activated neutral protease that modifies its substrates via limited proteolysis. His specialty was basic biochemistry, and he, for the first time in the history of proteolysis research, devised a universally applicable immunochemical method that can distinguish proteolytic products from the full-length substrates. The antibodies that created have been widely used in both basic and clinical studies worldwide (see a review, Saido et al., FASEB J, 1994). He then began collaborating with neurosurgeons and neuropathologists on brain ischemia and Alzheimer's disease (AD), respectively. The collaborations were so successful that in the 1990’s he decided to dedicate most of his time and effort to the study of the brain disorders as a Laboratory Head of RIKEN Brain Science Institute/Center for Brain Science. Although both brain ischemia (strokes) and AD cause dementia, the former had become more preventable by controlling vascular aging, whereas it has been still extremely difficult to stop the onset or to slow down the progression of AD, making him more inclined to study the latter. After discovering that amyloid b peptide (Ab) starting with pyroglutamate at positions 3 (Ab_N3pE) is a major species that accumulates in human brain (Saido et al., Neuron, 1995), he became interested in the catabolic mechanism of Ab. Using biochemical and reverse genetic methods, he discovered neprilysin (neutral endopeptidase) as a major in vivo Ab-degrading enzyme (Iwata et al., Nat Med, 2000; Science 2001). He hypothesized that an aging-dependent decline of neprilysin expression in the human brain may be one of the causes of sporadic AD. In the Science paper, he also predicted the possible presence of risk alleles in the MME gene encoding neprilysin, and a recent Genome-wide association study (GWAS) consistently identified two MME SNPs significantly associated with the incidence of sporadic AD (Bellenguez et al., Nat Genetics, 2022). In the course of identifying drug target(s) with specific emphasis on neprilysin, he discovered that binding of somatostatin to a somatostatin receptor heterodimer composed of subtypes 1 and 4 selectively increases neprilysin expression/activity (Saito et al., Nat Med, 2005; Saido et al. Japanese Patent 7099717, 2022), He now focuses on generating the GPCR-based medications that will be more specific/effective, safer, and more economical than immunotherapies for treating preclinical AD. His laboratory also created the world’s first single App knock-in mouse models that reconstitute AD pathology without depending on overexpression paradigm (Saito et al., Nat Neurosci, 2014); the models are being used by more than 800 groups worldwide. Consequently, he has become one of the highly cited scientists in the research community.

Affiliations and expertise

Laboratory Head, RIKEN Center for Brain Science

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

Health