Table Of ContentParkinson’s and
Alzheimer’s Today
About Neurodegeneration
and its Therapy
Lars P. Klimaschewski
123
Parkinson’s and Alzheimer’s Today
Lars P. Klimaschewski
Parkinson’s
and Alzheimer’s Today
About Neurodegeneration and its
Therapy
Lars P. Klimaschewski
Institute for Neuroanatomy
Medical University
Innsbruck, Austria
ISBN 978-3-662-66368-4 ISBN 978-3-662-66369-1 (eBook)
https://doi.org/10.1007/978-3-662-66369-1
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer-Verlag GmbH, DE, part
of Springer Nature 2022
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Dedicated to my parents
Preface
This book is addressed to all those who want to be informed about the state
of research on aging and cell death in the central nervous system. The early
development and degeneration of our brain later in life are described with
reference to recent research findings. The book is aimed at a readership inter-
ested in neurobiology or medicine and deals with the following questions:
Why do we need billions of nerve cells? What distinguishes our brain from
that of other mammals? Why does only man think in a complex language
and plan his actions far into the future? Which parts of the brain are par-
ticularly important for this ability? Why do nerve cells fail in old age? What
cell biological mechanisms are responsible for this? What exactly happens
in Parkinson’s and Alzheimer’s disease? Can the progression of neuronal cell
death be delayed or even stopped? What new therapies for dementia and
Parkinson’s might be available in the future? Those who are willing to look
behind the laboratory doors of neuroscientific research together with the
author will receive answers to these questions.
In the first chapter of this book, the basic structure and development of
our brain is outlined. The discussion of comparative aspects makes it clear
why we need billions of nerve cells in contrast to most animal species. Only
with this large number of building blocks, which function as nodes in the
multitude of neuronal networks, are the typical human abilities made pos-
sible. I will point out the essential differences between humans and other
mammals and refer to the neuroanatomical pecularities of our brain that
explain how higher cognitive performance is achieved.
vii
viii Preface
In the second part of the book, the consequences of the loss of neurons
will be in the foreground. Early on, neurons perish every day (by the age of
80, around a third of all nerve cells in the brain are lost). That this happens
largely unnoticed, we owe to a pronounced back-up. The most important
information is stored several times in different neuronal networks, so that
vital functions usually remain well preserved into old age. For people suffer-
ing from a neurodegenerative disease, however, this looks quite different. In
addition to the biological basics of aging, this chapter therefore deals with
the cellular processes that underlie Parkinson’s and Alzheimer’s disease in
more detail. The focus is on the development of both diseases from a neu-
ropathological point of view, less on the medical side. This book is there-
fore not intended to replace the medical textbook, but to supplement it with
neurobiological aspects.
The third chapter deals with the different options we have to delay or
even stop neuronal degeneration. In the future, it may be possible to com-
pensate for lost neurons by enhancing the formation of new nerve cells, the
so-called neurogenesis. The currently available therapeutic approaches for
the treatment of neuronal degeneration are also presented. However, the
focus is on new research results leading to novel therapeutic strategies to
treat Parkinson’s and Alzheimer’s disease.
This book uses work published by leading neuroscientists and physicians
worldwide. Their latest work is listed at the end of the chapters (without
claiming to be complete). The schematic drawings were created using com-
mercially available templates (https://www.motifolio.com/). What is special
about this book is that it will never be finished. Regularly I will present the
latest and most relevant developments from the Alzheimer’s and Parkinson’s
laboratories in Klima’s Brain Blog (https://www.klimasbrainblog.com/en).
On my website you may also want to subscribe to a newsletter that will
keep you up to date.
I would like to express my special thanks to my family and my colleagues
and friends for their corrections and comments, in particular to Annegret
Wehmeyer, Gerrit Krupski, Dietrich Lorke, Erich Brenner, Christian
Humpel, Willi Eisner and Maximilian Freilinger. Furthermore, I would
like to thank Dr. Christine Lerche and Claudia Bauer from Springer-
Verlag for their support. Finally, I would like to thank all the students of
the Universities of Heidelberg and Innsbruck who have attended my lectures
and seminars over the years and discussed the development and aging of the
brain with me. Some of the aspects discussed in this book go back to these
conversations.
Preface ix
Most of the conclusions reported here are based on generally accepted
and confirmed scientific results, however, some questions remain open and
require further investigation. But that’s how science works. Elaborate exper-
iments are carried out in the laboratory and large data sets are generated.
With much skepticism, these are then checked and often discarded, because
the following sentence by Charles Darwin, the discoverer of the theory of
evolution, applies more than ever: “False facts are extremely harmful to the
progress of science, because they often persist; false theories, on the other
hand, which are supported by some evidence, do no harm; because everyone
strives with praiseworthy zeal to prove their incorrectness”.
Contents
1 Introduction to Brain Development: Why do We Need
so Many Nerve Cells? 1
1.1 Neurons and Glia in the Central Nervous System 3
1.2 What Happens During Brain Development? 4
1.3 Evolutionarily Old Brain Parts are Simpler in Structure
than the Neocortex 6
1.4 What Distinguishes the Left from the Right Brain? 8
1.5 Brain Development in Childhood and Adolescence 9
1.6 The Child’s Brain is Enormously Plastic and can
Still Heal 10
1.7 Is a Large Brain “Smarter” than a Small One? 11
1.8 Absolute and Relative Brain Weight 14
1.9 With the Second Evolutionary Leap, Our Brain
Reaches its Maximum Size 16
1.10 Neural Stem Cells Remain Capable of Dividing
for a Long Time 18
1.11 The Frontal Lobe is Especially Important for
Higher Brain Functions 19
1.12 The Prefrontal Cortex Encodes Human Specific
Properties 21
1.13 Brain Performance in Comparison 23
Further Reading 25
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xii Contents
2 Aging and Neurodegenerative Diseases: Why do Nerve
Cells Die? 27
2.1 The Normal Aging Process 28
2.1.1 Mechanisms of Cellular Aging 30
2.1.2 Neuronal Cell Death 41
2.1.3 Blood Supply of the Aging Brain 45
2.2 Parkinson’s Disease 48
2.2.1 General Pathomechanisms 48
2.2.2 Special Morphology of Affected Neurons 56
2.2.3 Specific Causes of Parkinson’s Disease 60
2.2.4 Alpha-synuclein: A Key Protein in Parkinson’s
Disease 63
2.2.5 The Prion Theory of Parkinson’s Disease 67
2.3 Dementia and Alzheimer’s Disease 71
2.3.1 How Does Alzheimer’s Disease Manifest Itself? 72
2.3.2 General Pathomechanisms 74
2.3.3 The Disturbed Protein Homeostasis
in Alzheimer’s Disease 80
2.3.4 Tau Pathology 82
2.3.5 The Prion Theory in Alzheimer’s Disease 88
2.4 Inflammatory Components of Alzheimer’s
and Parkinson’s Disease 91
2.5 Viral Infections in Neurodegenerative Diseases 94
Further Reading 97
3 Saving or Replacing Nerve Cells: Which Strategy
is More Successful? 105
3.1 Parkinson’s Disease 108
3.1.1 Pharmacological Therapy 108
3.1.2 Surgical and physical therapy 109
3.1.3 Therapy with Neurotrophic Factors 111
3.1.4 Therapy with Antisense Oligonucleotides 114
3.1.5 Alpha-synuclein Aggregation Inhibitors
and Specific Immunotherapy 117
3.1.6 Stem Cell Therapy 117
3.1.7 Other Causal Therapeutic Approaches 119
3.2 Dementia and Alzheimer’s Disease 120
3.2.1 Cholinergica 120
3.2.2 Therapy with Secretase Inhibitors 121
3.2.3 Therapy with Neurotrophic Factors 122
