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Bursting Neurons and Fading Memories - 1st Edition - ISBN: 9780128019795, 9780128019887

Bursting Neurons and Fading Memories

1st Edition

An Alternative Hypothesis of the Pathogenesis of Alzheimer’s Disease

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Author: Michael R. D'Andrea
Paperback ISBN: 9780128019795
eBook ISBN: 9780128019887
Imprint: Academic Press
Published Date: 20th October 2014
Page Count: 170
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Advances in Alzheimer’s disease (AD) research have been challenging and without major breakthroughs in understanding its pathological basis. The reigning hypothesis suggests AD is the result of extracellular amyloid deposition that seed to form amyloid plaques, which then grow and kill neighboring neurons. However, there are several inconsistencies with this hypothesis, not to mention the inability to show clinical benefit in several failed clinical trials by pharmaceuticals (i.e., from Pfizer, Eli Lilly, etc.), and it is in the field’s best interest to explore and test multiple hypotheses for pathology rather than drive the majority of research on this single amyloid theory. Reviewing many scientifically peer-reviewed publications, this book describes the "Inside-Out" hypothesis on how amyloid escapes the circulatory system through a dysfunctional blood-brain barrier to bind to the alpha 7 nicotinic acetylcholine receptor on pyramidal neurons. Over time, excessive amounts of amyloid appear to be internalized, resulting in neuron death and lysis. This simple mechanism readily explains plaque composition, size, shape, and location. Based on the current direction of research in the field, this hypothesis appears years from any research and development.

Key Features

  • The clear, compelling, and unifying "Inside-Out" hypothesis of AD is brought to life through a string of scientific publications, synthesizing many known features of disease pathology
  • A high-level text on AD pathology, and suggestions for progress in a stagnating field
  • Point-by-point discussion on the issues surrounding the current amyloid cascade, and possible reasons why current clinical trials have failed
  • Contains high-quality photomicrographs in support of the "Inside-Out" hypothesis using single, double, and triple immunohistochemistry on human AD CNS tissues
  • Chapters address the need for a unifying plaque nomenclature, the importance of intracellular amyloid, the blood-brain barrier, inflammation, and autoimmunity

Table of Contents

  • Dedication
  • About the Author
  • Preface
  • Acknowledgments
  • Introduction
  • Chapter 1: Alzheimer’s Disease Today
    • Abstract
    • Neurological factors
    • Non-neurological factors
    • The amyloid cascade
    • Looking ahead
  • Chapter 2: Seeds of a New Perspective
    • Abstract
    • Histology
    • Ready to start
  • Chapter 3: Introducing the “Inside-Out” Hypothesis
    • Abstract
    • Presentation time
  • Chapter 4: Addressing Technical Concerns
    • Abstract
    • Lipofuscin
    • Primary antibodies
    • Heat is the ticket
    • Antibodies
    • In situ ELISA
  • Chapter 5: The Good Intentions of Formic Acid
    • Abstract
    • Formic acid is the problem
    • Running like mascara
  • Chapter 6: Connecting MAP-2 and Cell Lysis
    • Abstract
    • Reverse logic
    • Diffuse plaques are benign
    • Troublesome end point
  • Chapter 7: Classifying Plaques
    • Abstract
    • Three dimensions
    • Multiple colors
    • Inflammation
    • Triple IHC
    • Microglia’s unanticipated location
    • The diffuse amyloid plaque
    • Diffuse–vascular amyloid plaques
    • Dense–vascular amyloid plaques and others
    • Call for a nomenclature
  • Chapter 8: When Is a Star Like a Plaque?
    • Abstract
    • Similar initial hypotheses
    • New technology
    • Reflections of a discovery
    • Reinforcing evidence
    • Star nomenclature
    • Scientific parallels
    • Composition
    • Closing comment
  • Chapter 9: The Inflammation Cascade
    • Abstract
  • Chapter 10: Innocent Aβ42
    • Abstract
  • Chapter 11: The Alpha 7 Nicotinic Acetylcholine Receptor
    • Abstract
  • Chapter 12: Immunoglobulin: Another Perpetrator
    • Abstract
    • Immunoglobulin neurons
    • Degenerating Ig-positive neurons
  • Chapter 13: Add AD to the List of Autoimmune Diseases
    • Abstract
  • Chapter 14: The BBB and BRB in AD
    • Abstract
    • BRB, a vascular harbinger
    • In vivo BBB support
  • Chapter 15: “Inside-Out” in the Field
    • Abstract
    • Neuronal death by amyloid (via vascular issues)
    • Neuronal death by ApoE4
    • Neuronal death by inflammation
    • Neuronal death by tau
    • Neuronal death by autoantibodies
    • Miscellaneous notes
  • Chapter 16: Alzheimer’s Disease Tomorrow
    • Abstract
    • State of the AD nation
    • Targeting the α7 receptor
    • Targeting Aβ42: not plaques
    • Targeting the BBB
    • Targeting inflammation
    • Biomarker discovery
    • Assessing BBB integrity via BRB
    • New work
    • Closing statement
  • Glossary


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© Academic Press 2015
20th October 2014
Academic Press
Paperback ISBN:
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About the Author

Michael R. D'Andrea

Michael R. D'Andrea

Dr. D’Andrea has a PhD in Cell and Developmental Biology and an MS in Molecular Biology. He has authored over 100 scientific publications, including invited review papers on Alzheimer’s disease, and co-invented 11 patents. His technical expertise is in the areas of histopathology/neuropathology, immunohistochemistry, and image analysis. Since 1996, he was Team Leader and Principal Scientist of Target Validation Team at Johnson & Johnson Pharmaceutical Research & Development. There he discovered and validated novel targets, biomarkers, and compounds to treat cancer, inflammatory diseases, and Alzheimer’s disease, and accepted numerous awards for these endeavors. Currently, he is president and histopathologist at Slidomics, LLC.

He has presented is Alzheimer’s research at the following sponsored international, national and regional meetings: Society of Neuroscience; International Conference on Alzheimer’s Disease and Related Disorders; The Alzheimer’s Imaging Consortium; and International Neurodegeneration in Alzheimer’s Disease, Parkinson’s Disease & Related Disorders. In addition, he spoke at various meetings at the Annual Biological Staining Commission, The National Disease Research Institute, University of Pennsylvania, and was invited to lead the AlzForum’s WebCast International discussion for the Alzheimer’s Disease Forum on the evidence that neuronal cell death in AD is due to an autoimmune mechanism. He was also invited to the Challenging Views Of Alzheimer’s Disease: Round II meeting to debate the inflammatory aspects of AD. In addition, he has reviewed international AD grants (Spain, Israel) and is on several scientific editorial boards.

He was one of the first to publish the presence of intracellular A42 in normal and AD neurons in 1999, first to hypothesize that plaques originate from neuronal lysis, first to report the presence of various plaques types in the AD brain, and first to provide morphological evidence of apoptotic neuronal death through an autoimmune mechanism in AD, suggesting that AD is an autoimmune disease. Most recently, he published a book entitled “Bursting Neurons and Fading Memories: An Alternative Hypothesis of the Neuropathology of Alzheimer’s Disease”. Furthermore, Michael has animated the “Inside-Out” hypothesis that is available on YouTube. Currently, he continues to post discussions on the matter.

Affiliations and Expertise

President, Slidomics, LLC, Wilmington, DE, USA


"In addition to presenting and supporting his specific hypothesis, the author succeeds in conveying a number of important points regarding scientific research in general and the IHC methods specifically.... The methodical approach described here, including the careful attention to possible sources of artifacts, is a realistic portrayal of the hard work required both in the laboratory and at the microscope." -- Dr. Rhein Parri, Senior Lecturer in Pharmacology, School of Life and Health Sciences, Aston University, Birmingham, UK, in Biotechnic and Histochemistry

"....This book will delight the scientifically savvy reader with a guided tour of the process.... Dr. D’Andrea chronicles the process of scientific discovery in an insightful way that takes the reader on a journey... If you wanted a window into Alzheimer’s brain, here it is..... As a neuroscientist in the field, I found this book to be incredibly informative to the way I think about Alzheimer’s pathogenesis." - Holly Brothers, Postdoctoral Fellow, The Ohio State University, Columbus, OH, USA on Amazon

"Bursting Neurons and Fading Memories by Dr. Michael D’Andrea is a good book to read for those interested in Alzheimer’s disease (AD), its past research failures and its future promises.... The book provides valuable and specific staining techniques, some of which Dr. D’Andrea has devised through trial and error, that remind me of Ramὁn y Cajal’s early trials with improving silver nitrate stains at the turn of the 20th century, to gather details about the neuron’s structure and to discover some novel facts about how it dies in the damaged nervous system. I highly recommend this book." - Jack de la Torre, MD, PhD, Professor of Neuropsychiatry (Adjunct), Department of Psychology, University of Texas at Austin, Austin, TX, USA

"....Anyone wishing a clear description of the essential findings and the resulting hypothesis without having to consult the primary research papers will find their wish fully granted here. The writing is clear, the editing careful, and the references sufficient to show the way to the most relevant literature...." - Keith A. Crutcher, PhD, Neuroscientist, in the Journal of Alzheimer's Disease 


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