Intracellular Consequences of Amyloid in Alzheimer's Disease PDF
Preview Intracellular Consequences of Amyloid in Alzheimer's Disease
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 AMSTERDAM(cid:129)BOSTON(cid:129)HEIDELBERG(cid:129)LONDON NEWYORK(cid:129)OXFORD(cid:129)PARIS(cid:129)SANDIEGO SANFRANCISCO(cid:129)SINGAPORE(cid:129)SYDNEY(cid:129)TOKYO AcademicPressisanimprintofElsevier AcademicPressisanimprintofElsevier 125LondonWall,LondonEC2Y5AS,UK 525BStreet,Suite1800,SanDiego,CA92101-4495,USA 50HampshireStreet,5thFloor,Cambridge,MA02139,USA TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UK Copyrightr2016ElsevierInc.Allrightsreserved. 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ForInformationonallAcademicPresspublications visitourwebsiteathttp://store.elsevier.com/ Publisher:MaraConner SeniorAcquisitionEditor: NatalieFarra SeniorEditorialProjectManager:KristiAnderson ProductionProjectManager:JuliaHaynes Designer:MattLimbert TypesetbyMPSLimited,Chennai,India 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
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