Intracellular Consequences of Amyloid in Alzheimer's Disease

206 Pages·2016·18.09 MB·English

by  D'Andrea

INTRACELLULAR
CONSEQUENCES OF AMYLOID
IN ALZHEIMER’S DISEASE
INTRACELLULAR
CONSEQUENCES
OF AMYLOID IN
ALZHEIMER’S
DISEASE
M R. D’A
ICHAEL NDREA
President,Slidomics,LLC,Wilmington,DE,USA
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Dedication
Idedicatethis book to:
(cid:129) Thosewho passed away from this dreadful disease,and those who
caringlydonated their loved ones’tissues to research.None of us
would have discovered so much without their ultimate contributions;
and those who haveAlzheimer’sdiseaseandtheirfamily’s
caregivers, for helpissoon on the way.
(cid:129) My wife Patty, my oldest daughterDr Michelleand her husband,
Kevin, my son Michael, and youngest daughter, Stephanie,allof
whom have given me endlesssupport and love.
(cid:129) My parents, Henryand Angela,for alltheir eternal love andsupport,
and especiallyfor buying my first microscopeas aChristmas gift
whenI was 7yearsold that set my scientific career in motion.
About the Cover
The figures below represent serial sections of human Alzheimer’s
disease brain tissues processed for immunohistochemistry using an
antibody to Aβ42 and using a negative control antibody. All nuclei are
stained blue with hematoxylin. Arrowheads demonstrate the alignment
of a set of five neurons in theserialsections.
In the left panel (and book cover), Aβ42-positive immunolabeling is
presented as brown staining. Prominent Aβ-positive immunolabeling is
present in the vascular smooth muscle cells (large solid red arrow), and in
many cells, including neurons (arrowheads) and astrocytes (small arrow).
An Aβ42-positive plaqueisdetected (open arrow). Also note the presence
of several unstained red blood cells in the vessel (stained pale blue), as
well as extracellular Aβ42-positive immunolabeling in a diffuse plaque
that seems to leak from the Aβ42-laden vessel (at the 3:00 position of
the vessel).
In the right panel, no detectable Aβ42 immunolabeling is observed
in the negative control, including the area of the unstained amyloid
plaque (open arrow). The asterisk near the neuron in the negative control
shows the presence of intraneuronal lipofuscin (yellow-brown pigment
that is typically observed in neurons as granules composed of lipid-
containing residues of lysosomal digestion). (40x objective; courtesy of
Slidomics, LLC.)
ix
About the Author
Michael R. D’Andrea received his PhD in Cell and Developmental
BiologyandMSinMolecularBiology.Hehasauthoredover100scientific
publications, including invited review papers on Alzheimer’s disease
(AD), and coinvented 11 patents. His technical expertise is in the areas
of histopathology/neuropathology, immunohistochemistry, and image
analysis.Since1996,hewasTeamLeaderandPrincipalScientistofTarget
Validation Team at Johnson & Johnson Pharmaceutical Research &
Development. There he discovered and validated novel targets, biomar-
kers,andcompoundstotreatcancer,inflammatorydiseases,andAD,and
acceptednumerousawardsfortheseendeavors.Currently,heispresident
andchiefhistopathologistatSlidomics,LLC.
He has presented his Alzheimer’s research at the following sponsored
international, national, and regional meetings: Society of Neuroscience;
International Conference on AD and Related Disorders; The Alzheimer’s
Imaging Consortium; and International Neurodegeneration in AD,
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 wasinvited to
lead the AlzForum’s WebCast International discussion for the AD Forum
on the evidence that neuronal cell death in AD is due to an autoimmune
mechanism.HewasalsoinvitedtotheChallengingViewsofAD:RoundII
meeting to debate the inflammatory aspects of AD. In addition, he has
reviewedinternationalADgrants(Spain,Israel)andisonseveralscientific
editorialboards.
He was one of the first to relate the presence of intracellular Aβ42 in
AD neurons to senile, dense-core plaque formation not by deposition,
but through neuronal lysis that triggers the inflammatory responses that
inflict to additional neuronal death, independent of Aβ. He character-
ized the existence of plaques types based on their origin of formation
and provided histopathological 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 AD.
Furthermore, Michael has animated the “Inside-Out” (or “Bursting”)
hypothesis (available on YouTube (https://www.youtube.com/watch?
v5_NTaGjQow1c), now renamed the “Lytic Model” in this book.
Currently, he continuesto post discussionson the matter.
xi
Preface
Analyzing hundreds of publications on a nuanced topic, selecting
articles accurately and coherently to reflect the research, and then to tie
these together intoameaningfulstoryto allowyou,thereader,toaccess
this compilation has been a challenging task for me. A related difficulty
was deciding on the scope of this anthology. I will not try to represent
the multitude of aspects of a single medical condition, but will focus on
a single, critical aspect of a specific area of related research. This is to
drawclarityandattention toanotherwiseneglectedandconfusedtopic,
and to develop a novel hypothesis from an unbiased presentation of
established, documented facts.
As you picked up this book, you will know the medical condition in
question is Alzheimer’s disease (AD), and the specific area of research
is the intracellular consequences of amyloid. Researchers and scientists
studying AD will immediately recognize the importance of amyloid
senile plaques, one of the earliest discovered pathological attributes of
the debilitating condition, and a focal point of many clinical trials inves-
tigating a cure. Most of what we know about the pathology of AD is
focused around the amyloid protein, or specifically Aβ, the smaller
reportedly toxic fragment that comprises the plaques. Those studies
taught us how Aβ is generated and processed into additional fragments,
how neurons secrete it, how the toxic Aβ aggregates outside the neuro-
nal cells to form plaques, and how these extracellular plaques eventu-
ally cause neuronal death leading to AD.
The sequence of neuronal secretions of Aβ leading to neuronal death
is the basis of the “amyloid cascade hypothesis” and of a number of
clinical efforts aimed to reduce or remove levels of Aβ in AD patients.
Unfortunately, these clinical trials failed to alter the course of the dis-
ease even though significant reductions of Aβ levels and plaques were
observed. So if it seems that Aβ does not hold the key in curing AD
after all, then why spend your time readinga book about amyloid?
The failing strategy may not be amyloid per se, but the specific
targetingof the “extracellular” amyloid.
“Intracellular” Aβ in the neurons and other cells has often been
ignored because while we do know a great deal about the properties of
Aβ thanks to the collective efforts of many gifted scholars, many of their
perspectives have narrowly considered the protein only in its assigned
xiii
xiv
PREFACE
“extracellular” role as defined by the amyloid hypothesis. In other
words, although intracellular amyloid was detected in neurons, its pres-
ence was merely considered a source of the extracellularly secreted
amyloid.
Intracellular Aβ may have a more significant relationship to neuronal
death and disease than the extracellularly deposited Aβ. This single and
once unpopular change of perspective could be the key to all of the
pathological events leading to AD and is worth the time to understand
before turning our sights away from Aβ entirely.
To set the stage, chapters “Amyloid Basis of Alzheimer’s Disease”
and “Origin(s) of Intraneuronal Amyloid” present a brief historical
backgroundofamyloid,howAβisgeneratedandprocessed,howitrelates
totheamyloidcascadehypothesis,andmostimportantly,thepossibleori-
gins of the intraneuronal amyloid. Chapter “Natural Intracellular
ConsequencesofAmyloid”analyzestheunfamiliarcharacteristicsofAβas
a necessary component in a myriad of natural physiological processes in
neuronal and nonneuronal cells, while chapters “Pathological
Consequences of Aβ from Extracellular to Intraneuronal,” “Intraneuronal
Amyloid and Plaque Formation,” “Intraneuronal Amyloid and Cognitive
Impairment,” and “Intraneuronal Amyloid and Inflammation” present
information of the emerging pathological aspects of intraneuronal amyloid
anditsrelationshiptoamyloidplaqueformation,tocognitiveimpairment,
and inflammation, respectively. In chapter “Consequences of Intracellular
Amyloid in Vascular System”, the intracellular consequences of Aβ are
presented in nonneuronal cells such as the smooth muscle cells and
pericytes as related to pathologies in the AD vascular system. In closing,
the implications of intracellular Aβ are discussed in chapter “Implications
ofIntraneuronalAβ”.
While the role of intracellular amyloid in Alzheimer’s disease
remains undiscovered, an increasing body of work suggests that the
early pathogenesis of Alzheimer’s begins with the accumulation of Aβ
in neurons leading to their demise, and subsequent neuronal death
independent of Aβ. However, upstream from neuronal death may be
cell death of the vascular cells due to overaccumulation of Aβ as well,
leading to a dysfunctional blood-brain barrier that leaks toxic levels of
Aβ into the brain. Thus, I present this anthology to bolster research
endeavors inthis area to cure AD.
Acknowledgments
Especially to my immediate family for providing direction, style, and
edits for the book.
To all of the hundreds of esteemed colleagues cited in this book and
to those unintentionally overlooked; this book is a treasure of their con-
tributions, which is a testament of their precious time dedicated to help
cure Alzheimer’s disease. And for those authors who committed many
exhaustive hours publishing their review articles. This book would not
have been written ifit wasn’t for their work.
Thank You!
xv
Introduction
Alzheimer’s disease (AD): ultimately waiting for most people if they
live long enough. The statistics prove it, and chances are that you know
someone personally affected by this dreadful disease. As of 2015, there
are 5.3 million sufferers in the United States, and 47.5 million world-
wide; that’s more than the total population of Canada.1 Just this single
statisticaloneisstaggering.Itisestimatedthatabout75.6millionpeople
worldwide willhave Alzheimer’s in the next 15 years ifthere is no cure.
The cause(s) of this progressive and fatal disease remain(s) unknown,
and in spite of decades of research and bountiful funding, science has
only been able to treat the symptoms without stopping the deleterious
progression of the disease toward death.
AD is mostly associated with advanced age, and the clinical presenta-
tions of this neurodegenerative disorder are quite clear: marked decline
inmemoryandcognitiveperformance,includingimpairmentoflanguage,
visual and motor coordination, calculation, judgment and planning,
and problem solving, leading to eventual death.2,3 The neuropathological
features are also quite clear: significant synaptic loss (20(cid:1)50%), neuronal
deaththroughoutmanyareasinthebrain,withparticulardegenerationof
neuronsinthecerebralcortexandhippocampus,intracellularneurofibril-
larytangles,senileamyloidplaques,andgliosis.4
Just about every scientific paper, review, and editorial begins with
the same text citing these AD hallmarks while noting “the cause(s)
of this disease remain(s) unknown.” Hence, hypotheses need to be
generated to help determine the cause(s) of AD in an effort to provide a
therapeutic opportunity for the cure.
Of the many hypotheses presented over the 201 years, one hypothe-
sis has generated the most interest and support, the amyloid cascade
hypothesis. Hundreds of publications convincingly portrayed Aβ and
Aβ42, the smaller fragmented amyloid species, as toxic, despite prior
reports that seemed to leave little doubt that Aβ serves essential roles in
synaptic plasticity, learning, memory, and survival, not to mention non-
neuronal roles in cellular proliferation, wound healing, and more
recently, as an antimicrobial.
Thereportsportrayingthetoxicnatureoftheseamyloidprecursorpro-
tein (APP) products are the building blocks of the amyloid hypothesis,
whichstatesthatincreasedAβproductionandsubsequentsecretionbythe
neurons(orfailureofAβclearance)inducesagradualAβaccumulationin
xvii