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The authors grant unrestricted publishing and distribution rights to the publisher. The electronic versions of the chapters are published under Creative Commons Attribution-NonCommercial 4.0 International (<a href="https://creativecommons.org/licenses/by-nc/4.0/" target="_blank" rel="noopener">CC BY-NC 4.0</a>). Users are allowed to share and adapt the chapters for any non-commercial purposes as long as the authors and the publisher are explicitly identified and properly acknowledged as the original source. The books in their entirety are subject to copyright by the publisher. The reproduction, modification, republication and display of the books in their entirety, in any form, by anyone, for commercial purposes are strictly prohibited without the written consent of the publisher.</p> Front Matter https://exonpublications.com/index.php/exon/article/view/229 <p>&nbsp;</p> <p>&nbsp;</p> ALZHEIMER'S DISEASE Thomas Wisniewski, MD (ed) Copyright (c) 2019 https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 10.15586/alzheimersdisease.2019 Foreword https://exonpublications.com/index.php/exon/article/view/230 <p>Alzheimer’s disease (AD) is the sixth leading cause of death in the USA. Globally about 50 million individuals have AD or related dementias. With the increasing average age of humans worldwide, the total number of people with dementia is projected to reach 82 million by 2030 and 152 million by 2050. Despite its prevalence, AD is the only cause of death among the top 10 causes of death globally for which no effective pharmaceutical agents exist to halt or slow down the disease progression. By some estimates, AD and related dementias are the single most expensive medical condition. In 2019, direct costs of AD in the USA will be ~$290 billion, which is expected to rise to ~$1.1 trillion by 2050 if no treatments are developed. Hence, there is a tremendous imperative to gain a better understanding of the pathogenesis of AD and to develop effective treatments. AD is a complex, multifactorial disease, which is unique to humans. AD is defined neuropathologically by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the vasculature (known as congophilic amyloid angiopathy [CAA]), and abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Pathological aggregation of phosphorylated tau and Aβ occurs in a sequential process. Monomers first aggregate into oligomers intraneuronally that then further aggregate into the fibrils observed in amyloid plaques and NFTs. This pathology then spreads in a characteristic brain topography that is distinct for NFTs and plaques. This process develops over many years, with a preclinical period of two to three decades, the onset of which is modulated by apolipoprotein E (apoE) genotype, as well as other genetic and environmental risk factors. <a href="https://exonpublications.com/index.php/exon/article/view/230/295" target="_blank" rel="noopener">CONTINUE READING.....</a></p> Fernando Goni Copyright (c) 2019 Fernando Goni https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 vii vii 10.15586/alzheimersdisease.2019.fr Preface https://exonpublications.com/index.php/exon/article/view/231 <p>Alzheimer’s disease (AD) is the most common cause of dementia. The term “dementia” is derived from the Latin word <em>demens</em>, meaning “being out of one’s mind,” and has been used since the 13th century. AD has been recognized as a distinct entity since the publication of Alzheimer’s description of a patient with presenile dementia in 1906. The first biochemical identification of amyloid beta (Aβ) as the major component of amyloid plaques, a key neuropathological lesion in AD, was published in 1984 with the seminal work of Dr. George Glenner. The latter discovery led to the amyloid cascade hypothesis of AD, with a focus on developing amyloid directed therapeutic approaches. The latter have all failed in clinical trials thus far. More recently, there is growing body of genetic, transcriptomic, and proteomic data pointing to the complexity of AD pathogenesis. This has resulted in a greater diversity of therapeutic approaches being attempted—in effect, resulting in “more shots on goal,” with the prospect that at least some of these approaches will be efficacious. Hence, despite the many failures of AD therapeutic clinical trials, this is a hopeful time in AD research. There is a growing anticipation that our greater understanding of the underlying multifactorial pathogenesis of AD will result in effective therapeutic interventions in the near future. <a href="https://exonpublications.com/index.php/exon/article/view/231/296" target="_blank" rel="noopener">CONTINUE READING…..</a></p> Thomas Wisniewski Copyright (c) 2019 Thomas Wisniewski https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 ix ix 10.15586/alzheimersdisease.2019.pr Contributors https://exonpublications.com/index.php/exon/article/view/232 <p><strong>ABRAHAM O. SAMSON, PHD</strong><br>Drug Discovery Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel</p> <p><strong>ALEXANDER PILOZZI, BS</strong><br>Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA</p> <p><strong>ANA I. RAMÍREZ, PHD</strong><br>Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Universidad Complutense de Madrid, Spain; Facultad de Óptica y Optometría, Universidad Complutense de Madrid, Spain</p> <p><strong>ANDREAS M. GRABRUCKER, PHD</strong><br>Cellular Neurobiology and Neuro-Nanotechnology Lab Department of Biological Sciences, University of Limerick, Limerick, Ireland; Bernal Institute, University of Limerick, Limerick, Ireland; Health Research Institute (HRI), University of Limerick, Limerick, Ireland</p> <p><strong>ANNA MARIA JADWIGA WEGIEREK, PSY D</strong><br>Wegierek Psychology Centerm Wegierek Psychology Center, Inc, Chicago, IL, USA</p> <p><strong>ANTONIETTA VILELLA, PHD</strong><br>Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy</p> <p><strong>ANUSHKA KHASNOBISH, MSC</strong><br>Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan</p> <p><strong>ASTRID NORBERG, RN, PHD</strong><br>Department of Nursing, Umeå University, Umeå, Sweden; Palliative Research Center, Ersta Sköndal Bräcke University College, Stockholm, Sweden</p> <p><strong>BARBARA KRAMARZ, PHD</strong><br>Functional Gene Annotation, Preclinical and Fundamental Science, UCL Institute of Cardiovascular Science, University College London,, London, UK</p> <p><strong>BARUH POLIS, MD</strong><br>Drug Discovery Laboratory, The Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel</p> <p><strong>CEMIL TUMER, PHD</strong><br>Department of Physiology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey</p> <p><strong>CHIARA A. DE BENEDICTIS, MSC</strong><br>Cellular Neurobiology and Neuro-Nanotechnology Lab, Department of Biological Sciences, University of Limerick, Limerick, Ireland</p> <p><strong>ELEANOR DRUMMOND, PHD</strong><br>Brain and Mind Centre and Central Clinical School, Faculty of Medicine and Health, University of Sydney, Australia</p> <p><strong>ELENA SALOBRAR-GARCIA, PHD</strong><br>Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Universidad Complutense de Madrid, Spain</p> <p><strong>ENVER AHMET DEMIR, MD, PHD</strong><br>Department of Physiology, Faculty of Medicine, Hatay Mustafa Kemal University Hatay, Turkey</p> <p><strong>HATICE DOGAN, MS, PHD.C</strong><br>Department of Physiology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey</p> <p><strong>HIDETOSHI MORITA, PHD</strong><br>Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan</p> <p><strong>INÉS LÓPEZ-CUENCA, MSC</strong><br>Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Universidad Complutense de Madrid, Spain</p> <p><strong>ISRAEL MARTÍNEZ-NICOLÁS, MSC</strong><br>Instituto de Neurociencias de Castilla y León,, Universidad de Salamanca, Spain; Departamento de Psicología Básica Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Salamanca, Spain</p> <p><strong>JOSE FERNÁNDEZ-ALBARRAL, MSC</strong><br>Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Universidad Complutense de Madrid, Spain</p> <p><strong>JOSÉ M. RAMÍREZ, MD, PHD</strong><br>Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Universidad Complutense de Madrid, Spain; Facultad de Medicina, Universidad Complutense de Madrid, Spain</p> <p><strong>JUAN CARRO, PHD</strong><br>Instituto de Neurociencias de Castilla y León, Universidad de Salamanca, Spain;, Departamento de Psicología Básica Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Salamanca, Spain</p> <p><strong>JUAN J. SALAZAR, PHD</strong><br>Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Universidad Complutense de Madrid, Spain;, Facultad de Óptica y Optometría, Universidad Complutense de Madrid, Spain</p> <p><strong>JUAN JOSÉ GARCÍA MEILÁN, PHD</strong><br>Instituto de Neurociencias de Castilla y León, Universidad de Salamanca, Spain; Departamento de Psicología Básica, Psicobiología y, Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Salamanca, Spain</p> <p><strong>KATARZYNA LESNIAK, PSY D</strong><br>Wegierek Psychology Center, Wegierek Psychology Center, Inc, Chicago, IL, USA</p> <p><strong>LINDSAY CRAWFORD, MS</strong><br>Exercise &amp; Memory Laboratory, Department of Health, Exercise Science, and Recreation Management, The University of Mississippi, MS,, USA</p> <p><strong>MARZENA UŁAMEK-KOZIOŁ, MD, PHD</strong><br>Laboratory of Ischemic and Neurodegenerative Brain Research, Mossakowski Medical Research Centre, Polish Academy of Sciences,, Warsaw, Poland; First Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland</p> <p><strong>OKAN TUTUK, MS, PHD.C</strong><br>Department of Physiology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay, Turkey</p> <p><strong>OLIVER WIRTHS, PHD</strong><br>Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany</p> <p><strong>PAUL D. LOPRINZI, PHD</strong><br>Exercise &amp; Memory Laboratory, Department of Health, Exercise Science, and Recreation Management, The University of Mississippi, MS, USA</p> <p><strong>PAULA GRAMMAS, PHD</strong><br>Department of Neuroscience, University of Rhode Island, Kingston, RI, USA</p> <p><strong>PILAR ROJAS, MD</strong><br>Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Universidad Complutense de Madrid, Spain;, Hospital Universitario, Gregorio Marañón, Madrid, Spain</p> <p><strong>ROSA DE HOZ, MD, PHD</strong><br>Instituto de Investigaciones Oftalmológicas Ramón Castroviejo, Universidad Complutense de Madrid, Spain; Facultad de Óptica y Optometría Universidad Complutense de Madrid, Spain</p> <p><strong>RUTH C. LOVERING, PHD</strong><br>Functional Gene Annotation, Preclinical and Fundamental Science, UCL Institute of Cardiovascular Science, University College London,, London, UK</p> <p><strong>RYSZARD PLUTA, MD, PHD</strong><br>Laboratory of Ischemic and Neurodegenerative Brain Research, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland</p> <p><strong>SASCHA WEGGEN, PHD</strong><br>Department of Neuropathology, Heinrich-Heine University, Duesseldorf, Germany</p> <p><strong>SHAN PATEL, MS</strong><br>Wegierek Psychology Center, Wegierek Psychology Center, Inc, Chicago, IL, USA</p> <p><strong>SILVIA ZAMPAR, MSC</strong><br>Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Göttingen, Germany</p> <p><strong>SŁAWOMIR JANUSZEWSKI, BS</strong><br>Laboratory of Ischemic and Neurodegenerative Brain Research, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland</p> <p><strong>STANISŁAW J. CZUCZWAR, MD, PHD</strong><br>Department of Pathophysiology, Medical University of Lublin, Lublin, Poland</p> <p><strong>SUZANNE M. DE LA MONTE, MD, MPH</strong><br>Department of Pathology and Laboratory Medicine, Providence VA Medical Center, Women and Infants Hospital of Rhode Island, and the Alpert Medical School of Brown University, Providence, RI, USA; Departments of Neurology, Neurosurgery, and Medicine, Rhode Island Hospital Providence, RI USA</p> <p><strong>THIDE E. LLORENTE, MSC</strong><br>Instituto de Neurociencias de Castilla y León, Universidad de Salamanca, Spain; Departamento de Psicología Básica Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Salamanca, Spain</p> <p><strong>THOMAS WISNIEWSKI, MD</strong><br>New York University Alzheimer’s Disease Center, New York University School of Medicine, New York, NY, USA</p> <p><strong>YULIYA BOGDANOVSKAYA, MS, LPC</strong><br>Wegierek Psychology Center, Wegierek Psychology Center, Inc, Chicago, IL, USA</p> <p><strong>YUSUKE FUJII, PHD</strong><br>Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan; Fundamental Laboratory, Ohayo Dairy Products Co., Ltd., Okayama, Japan</p> <p><strong>XUDONG HUANG, PHD</strong><br>Neurochemistry Laboratory, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA</p> List of Contributors Copyright (c) 2019 Chris Morais https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 xi xvii 10.15586/alzheimersdisease.2019.cont A New Perspective on Alzheimer’s Disease as a Brain Expression of a Complex Metabolic Disorder https://exonpublications.com/index.php/exon/article/view/233 <p><strong>ABSTRACT&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp;</strong></p> <p>Alzheimer’s disease (AD) is an irredeemable chronic neurodegenerative disorder and the predominant cause of dementia. The disease progression is associated with the deposition of amyloid plaques and formation of neurofibrillary tangles in the brain, yet clinical dementia is the end and culminating stage of the enduring pathology. Recent evidence suggests that AD is characterized by distinctive abnormalities apparent on systemic, histological, macromolecular, and biochemical levels. Besides the well-described characteristic profuse neurofibrillary tangles, dystrophic neurites, and Aβ deposits, the AD pathology includes substantial neuronal loss, inflammation, extensive DNA damage, considerable mitochondrial malfunction, impaired energy metabolism, and chronic oxidative stress. Moreover, severe metabolic dysfunction leading to oxidative stress is a possible cause and hallmark of AD that is apparent decades before the disease manifestation. State-of-the-art metabolomics studies have proved that arginine and branched-chain amino acids metabolism disturbances accompany AD and contribute to its pathogenesis. Repetitive failures to find an efficient anti-amyloid or anti-Tau treatment, which would face the challenges of the complex AD pathology, led to the hypothesis that hyperphosphorylated Tau and deposited Aβ proteins are hallmarks, not the ultimate causes of AD. Accordingly, the modern scientific vision of AD etiology and pathogenesis must reach beyond the hallmarks and look for alternative strategies and areas of research.</p> Baruh Polis Abraham O. Samson Copyright (c) 2019 Baruh Polis, Abraham O. Samson https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 1 22 10.15586/alzheimersdisease.2019.ch1 Gene Ontology: A Resource for Analysis and Interpretation of Alzheimer’s Disease Data https://exonpublications.com/index.php/exon/article/view/234 <p><strong>ABSTRACT&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp;&nbsp;</strong></p> <p>Gene Ontology (GO) is a universal resource for analyses and interpretation of high-throughput biological datasets. GO is developed and curated by several different groups, based at scientific institutions around the world, working together under the auspices of the GO Consortium. GO annotations capture biological functional knowledge by associating gene products with GO terms. GO term and gene product records all have computer-readable accession numbers; therefore, these annotations can be easily used for analyses of large datasets while retaining human-readable labels. The UCL Functional Gene Annotation group focuses on GO annotation of human gene products. Our group has led initiatives to systematically annotate proteins and microRNAs across specific biomedical fields, and our current biocuration effort, funded by the Alzheimer’s Research UK foundation, is focused on dementia and Alzheimer’s disease. Our group has also contributed to the development and revision of the ontology describing neurological domains of biology. Here we present an overview of GO and explain how our work, as well as the work of other members of the GO Consortium, is improving the neurological domains of the GO resource. These biocuration efforts will benefit the dementia and Alzheimer’s research community by rendering GO more suitable for analyses of neurological datasets.</p> Barbara Kramarz Ruth C. Lovering Copyright (c) 2019 Barbara Kramarz, Ruth C. Lovering https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 23 36 10.15586/alzheimersdisease.2019.ch2 Using Proteomics to Understand Alzheimer’s Disease Pathogenesis https://exonpublications.com/index.php/exon/article/view/235 <p><strong>ABSTRACT&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp;</strong></p> <p>Our current understanding of the molecular changes that drive Alzheimer’s disease (AD) pathogenesis is incomplete. Unbiased, mass spectrometry-based proteomic studies provide an efficient and comprehensive way to quantitatively examine thousands of proteins at once using microscopic amounts of human brain tissue. Recently, the number of proteomic studies that examine protein changes in AD brain tissue has been increasing. This chapter reviews the different proteomic approaches currently being used to identify pathological protein changes in AD brain tissue including bulk tissue studies that examine protein changes throughout the progression of AD, studies of the insoluble proteome in AD, studies using proteomics to examine selective vulnerability in AD, studies of the amyloid plaque and neurofibrillary tangle proteome, studies of the synaptic proteome, and studies of the interactome of beta amyloid and tau. Combined, these complementary proteomic approaches provide increased understanding about the protein changes that occur in the AD brain. Results from these proteomic studies provide an excellent resource for future hypothesis-driven targeted studies and will help identify new biomarkers of disease and new drug targets for AD.</p> Eleanor Drummond Thomas Wisniewski Copyright (c) 2019 Eleanor Drummond, Thomas Wisniewski https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 37 51 10.15586/alzheimersdisease.2019.ch3 Common Proteomic and Genomic Contribution to Ischemic Brain Damage and Alzheimer’s Disease https://exonpublications.com/index.php/exon/article/view/236 <p><strong>ABSTRACT</strong></p> <p>Ischemic brain damage is associated with the deposition of folding proteins, such as all fragments of the amyloid protein precursor and tau protein, in the intra- and extracellular spaces of neurons. In this chapter, we summarize the protein changes associated with Alzheimer’s disease and their gene expression (amyloid protein precursor and tau protein) after cerebral ischemia and their role in the ischemic etiology of Alzheimer’s disease. Recent advances in understanding the ischemic etiology of Alzheimer’s disease have revealed dysregulation of <em>amyloid</em> <em>protein precursors, β-secretase, presenilin 1 and 2, autophagy, mitophagy</em>, <em>apoptosis</em>, and <em>tau protein </em>genes after ischemic brain injury. However, reduced expression of mRNA of the α-secretase in cerebral ischemia causes neurons to be less resistant to injury. In this chapter, we present the latest evidence that Alzheimer’s disease-related proteins and their genes play a key role in brain damage with ischemia-reperfusion and that ischemic episode is an essential and leading provider of Alzheimer’s disease development. Understanding the underlying processes of linking Alzheimer’s disease-related proteins and their genes in brain ischemia injury with the risk of developing Alzheimer’s disease will provide the most significant goals for therapeutic development to date.</p> Ryszard Pluta Marzena Ułamek-Kozioł Sławomir Januszewski Stanisław J. Czuczwar Copyright (c) 2019 Ryszard Pluta, Marzena Ułamek-Kozioł, Sławomir Januszewski, Stanisław J. Czuczwar https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 53 68 10.15586/alzheimersdisease.2019.ch4 Contributing Factors of Neurodegeneration in Alzheimer’s Disease https://exonpublications.com/index.php/exon/article/view/237 <p><strong>ABSTRACT</strong></p> <p>Alzheimer’s Disease (AD) affects at least 5.7 million Americans, and it is the sixth leading cause of death in the United States. At the onset, patients experience minor memory problems. Next, impairments in speech and motor function manifest as a limitation to well-being and independence. Slowing this pandemic rise is critical, since AD also bears a huge socioeconomical burden. Unfortunately, there is limited prevention and no effective cure has been found, as all clinical trials for promising AD drugs have failed thus far. The pathological hallmarks of AD include amyloid-β plaques (Aβ), neurofibrillary tangles (NFT), and neuroinflammation. Other factors include <em>APOE4 </em>and environmental stressors, such as metal dyshomeostasis, which contribute to AD pathogenesis. Herein, we review major contributing factors involved in AD pathophysiology. Deeper understanding of associated molecular mechanisms underlying AD pathogenesis is critical for developing novel AD theranostics.</p> Breeya Tailor Alexander Pilozzi Xudong Huang Copyright (c) 2019 Breeya Tailor, Alexander Pilozzi, Xudong Huang https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 69 84 10.15586/alzheimersdisease.2019.ch5 The Role of Trace Metals in Alzheimer’s Disease https://exonpublications.com/index.php/exon/article/view/238 <p><strong>ABSTRACT</strong></p> <p>The extracellular aggregation of insoluble protein deposits of amyloid-β (Aβ) into plaques and the hyperphosphorylation of the intracellular protein tau leading to neurofibrillary tangles are the main pathological hallmarks of Alzheimer’s disease (AD). Both Aβ and tau are metal-binding proteins. Essential trace metals such as zinc, copper, and iron play important roles in healthy brain function but altered homeostasis and distribution have been linked to neurodegenerative diseases and aging. In addition, the presence of non-essential trace metals such as aluminum has been associated with AD. Trace metals and abnormal metal metabolism can influence protein aggregation, synaptic signaling pathways, mitochondrial function, oxidative stress levels, and inflammation, ultimately resulting in synapse dysfunction and neuronal loss in the AD brain. Herein we provide an overview of metals and metal-binding proteins and their pathophysiological role in AD.</p> Chiara A. De Benedictis Antonietta Vilella Andreas M. Grabrucker Copyright (c) 2019 Chiara A. De Benedictis, Antonietta Vilella, Andreas M. Grabrucker https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 85 106 10.15586/alzheimersdisease.2019.ch6 N-Terminally Truncated Aβ Peptide Variants in Alzheimer’s Disease https://exonpublications.com/index.php/exon/article/view/239 <p><strong>ABSTRACT</strong></p> <p>The accumulation and aggregation of amyloid-β (Aβ) peptides in the brain is believed to be the initial trigger in the molecular pathology of Alzheimer’s disease (AD). In addition to the widely studied full-length Aβ peptides (mainly Aβ<sub>1–40</sub> and Aβ<sub>1–42</sub>), a variety of amino-terminally truncated (N-truncated) peptides, such as Aβ<sub>pE3-x</sub> and Aβ<sub>4-x</sub>, have been detected in high abundance in autopsy samples from sporadic and familial AD patients. N-truncated Aβ species adopt specific physicochemical properties resulting in a higher aggregation propensity and increased peptide stability, which likely account for their neurotoxic potential. The presence of N-truncated Aβ peptides in transgenic mouse models of AD and the selective overexpression of specific N-truncated variants in the murine brain have facilitated their investigation in relevant in vivo settings. In this chapter, we address the pathological relevance of N-truncated Aβ peptide species and summarize the current knowledge about the enzymatic activities that might be involved in their generation.</p> Oliver Wirths Silvia Zampar Sascha Weggen Copyright (c) 2019 Oliver Wirths, Silvia Zampar, Sascha Weggen https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 107 122 10.15586/alzheimersdisease.2019.ch7 Insulin Resistance and Oligodendrocyte/Microvascular Endothelial Cell Dysfunction as Mediators of White Matter Degeneration in Alzheimer’s Disease https://exonpublications.com/index.php/exon/article/view/240 <p><strong>ABSTRACT</strong></p> <p>In Alzheimer’s disease (AD), white matter (WM) degeneration begins early, increases with disease progression, and contributes to cognitive impairment, yet the mechanisms are poorly understood. This article reviews the roles of myelin loss, oligodendrocyte dysfunction, and microvasculopathy in relation to AD WM degeneration. Myelin loss impairs axonal function and its breakdown promotes oxidative stress, inflammation, and lipid peroxidation, further compromising the structure and function of axons. Oligodendrocyte dysfunction impairs homeostatic mechanisms needed to maintain myelin. Microvascular disease with endothelial cell pathology leads to thrombin activation and pro-inflammatory cytokine release, oxidative stress, and increased vascular permeability. Progressive fibrotic replacement of smooth muscle cells reduces vaso-responsiveness to metabolic demands. Fibrotic thickening of vessel walls narrows the lumens, rendering them more susceptible to occlusion, endothelial cell injury, and thrombin activation. Since normal physiological functions of oligodendrocytes and microvascular endothelial cells rely on intact insulin/insulin-like growth factor (IGF) signaling through cell survival, metabolic and anti-inflammatory pathways, conceivably, WM degeneration in AD is mediated by insulin and IGF resistance with attendant pathogenic targeting of oligodendroglia and endothelial cells. The apolipoprotein E-ε4 genotype may serve as a co-factor in AD associated glial-vascular WM degeneration due to its role as a mediator of insulin resistance.</p> Suzanne M. de la Monte Paula Grammas Copyright (c) 2019 Suzanne M. de la Monte, Paula Grammas https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 123 145 10.15586/alzheimersdisease.2019.ch8 Relationship between Alzheimer’s Disease and the Human Microbiome https://exonpublications.com/index.php/exon/article/view/241 <p><strong>ABSTRACT</strong></p> <p>Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory and language disorders, and the accumulation of amyloid-β and tau protein in the brain has been considered a feature of AD. The accumulation of amyloid-β has been reported to be observed 15 to 20 years before the onset by image analysis-based diagnostic methods. In addition, it has been reported that AD is associated with various diseases such as type 2 diabetes, periodontal disease, and obesity. It is conceivable that these diseases trigger the onset of AD. The human gut and brain form a network called “brain–gut–microbiota axis,” and it is suggested that the gut microbiota is involved in brain diseases. Recently, the microbiota has also been reported to be involved in diseases such as depression and Parkinson’s disease, and so attention is being paid to the relationship between AD and gut microbiota. This chapter outlines the relationship between AD and the human microbiome.</p> Yusuke Fujii Anushka Khasnobish Hidetoshi Morita Copyright (c) 2019 Yusuke Fujii, Anushka Khasnobish, Hidetoshi Morita https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 147 158 10.15586/alzheimersdisease.2019.ch9 Ocular Exploration in the Diagnosis and Follow-Up of the Alzheimer’s Dementia https://exonpublications.com/index.php/exon/article/view/242 <p><strong>ABSTRACT</strong></p> <p>The retina is part of the central nervous system (CNS), and therefore, in Alzheimer’s disease (AD), retinal and optic nerve degeneration could take place. This degeneration leads to neurofunctional changes that can be detected early and followed up throughout the evolution of the disease. As opposed to other CNS structures, the eye is easily accessible for in vivo observation. Retinal organization allows for the identification of its different neurons, and in consequence, detection of minimal changes taking place during neurodegeneration is possible. Functional vision studies performed on AD patients in recent years have shown how visual acuity, contrast sensitivity, color vision, and visual integration vary with the progression of neurodegeneration. The development of optical coherence tomography in ophthalmology has meant a breakthrough in retinal exploratory techniques, allowing the obtention of high-resolution images using light. This technique enables retinal analysis in the earliest stages of AD, being considered as a biomarker of neuronal damage. Given AD’s high prevalence and its expected increase, it is important to perform easy tests that cause minimal discomfort to the patients at a low cost while offering abundant information on the stage of the disease.</p> Elena Salobrar-Garcia Rosa de Hoz Ana I. Ramírez Juan J. Salazar Pilar Rojas Inés López-Cuenca Jose Fernández-Albarral José M. Ramírez Copyright (c) 2019 Elena Salobrar-Garcia, Rosa de Hoz, Ana I. Ramírez, Juan J. Salazar, Pilar Rojas, Inés López-Cuenca, Jose Fernández-Albarral, José M. Ramírez https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 159 177 10.15586/alzheimersdisease.2019.ch10 The Deterioration of Semantic Networks in Alzheimer’s Disease https://exonpublications.com/index.php/exon/article/view/243 <p><strong>ABSTRACT</strong></p> <p>Language impairments in Alzheimer’s disease may appear at the prodromal stage. The most significant impairment is found at the lexical-semantic process level, which is explained either by a degradation of the areas that store the semantic network or by a failure at retrieving the information from that network. Regardless of the retrieval failure happening, there is evidence of the degradation of the semantic network at some levels. Several studies support the bottom-up breakdown, according to which the loss starts at the specific concept attribute level, along with the link with its coordinates, while superordinates are preserved. Some characteristics can affect this loss such as familiarity, age of acquisition, frequency, or affective features. While classic studies have focused on concrete neutral nouns, recent research is exploring the role of emotion. Since emotional processes strengthen the semantic relationship between concepts, it could be a relevant dimension for the preservation of the semantic network.</p> Israel Martínez-Nicolás Juan Carro Thide E. Llorente Juan José García Meilán Copyright (c) 2019 Israel Martínez-Nicolás, Juan Carro, Thide E. Llorente, Juan José García Meilán https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 179 191 10.15586/alzheimersdisease.2019.ch11 Alzheimer’s Disease: Memory Interference and the Role of Exercise https://exonpublications.com/index.php/exon/article/view/244 <p><strong>ABSTRACT</strong></p> <p>Alzheimer’s disease is an irreversible, progressive brain disorder that damages memory, behavioral, and cognitive skills. This condition causes brain cells to degenerate and die leading to many cognitive issues. Although the exact cause is unknown, it is thought to be due to a combination of genetic, lifestyle, and environmental factors. Due to its progressive nature, symptoms can vary from mild memory loss to complete lack of ability to respond to one’s surroundings. The memory impairments brought on by this disease can lead to specific problems with memory interference, which may be caused by dysfunction in working and semantic memory. When conducting experiments on Alzheimer’s patients, there is also the added difficulty of the individual having trouble remembering the instructions and needing external cues to complete memory tasks. This chapter outlines the disease, its symptoms, risk factors, how it affects memory, and how exercise may be a prevention and treatment option.</p> Lindsay Crawford Paul D. Loprinzi Copyright (c) 2019 Lindsay Crawford, Paul D. Loprinzi https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 193 204 10.15586/alzheimersdisease.2019.ch12 Sense of Self among Persons with Advanced Dementia https://exonpublications.com/index.php/exon/article/view/245 <p><strong>ABSTRACT</strong></p> <p>As humans, we have a sense of self, and at best, we are proud of our abilities and feel respected by other persons. Persons with dementia have been regarded losing their self. Quantitative research has shown that this is true, while qualitative research has shown that parts of self are severely affected while other parts remain even among persons with advanced dementia. These persons sometimes keep feeling “still the same” as before getting dementia. Their memory deficits help as does support from other persons. The theory of three aspects of self by the psychologists Rom Harré and Steven Sabat are presented, that is, the feeling that we are, who we are, and who we are together with other persons. Based on empirical research, suggestions will be given about how by promoting experiences of at-homeness, dignity, and being oneself related to others we can help persons with advanced dementia experience themselves as valuable persons.</p> Astrid Norberg Copyright (c) 2019 Astrid Norberg https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 205 221 10.15586/alzheimersdisease.2019.ch13 Depression in Alzheimer’s Disease: The Roles of Cholinergic and Serotonergic Systems https://exonpublications.com/index.php/exon/article/view/246 <p><strong>ABSTRACT</strong></p> <p>Although depression and Alzheimer’s disease fundamentally result from distinct pathophysiological events, their coincidence is far from a rare occurrence. In addition to the difficulty in the diagnosis of depression in the patients with a cognitive impairment, care givers and even physicians are mostly unaware that depression and Alzheimer’s disease can coexist. While depression has already a devastating impact on quality of life by itself, coinciding depression and Alzheimer’s disease may advance to a cataclysmic magnitude. This chapter underlines obstacles in the recognition of depression in the Alzheimer’s patients following a brief introduction to the concept of depression. Depression and Alzheimer’s disease appear to intersect in the cholinergic and serotonergic systems which may engender an exquisite strategy in the treatment of both disorders. Therefore, potential cholinergic and serotonergic targets are also emphasized.</p> Enver Ahmet Demir Okan Tutuk Hatice Dogan Cemil Tumer Copyright (c) 2019 Enver Ahmet Demir, Okan Tutuk, Hatice Dogan, Cemil Tumer https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 223 235 10.15586/alzheimersdisease.2019.ch14 A Collaborative Approach to Treatment of Alzheimer’s Disease from a Psychological Perspective https://exonpublications.com/index.php/exon/article/view/247 <p><strong>ABSTRACT</strong></p> <p>After the age of 60, earlier in many cases, patients who experience perseverations, forgetfulness, and difficulties with daily living are often referred by their physicians for a neuropsychological evaluation. A neuropsychological evaluation consists of a variety of tests that illustrate a patient’s cognitive functioning that include attention, concentration, verbal memory, visual memory, problem-solving, and cognitive flexibility. It further clarifies a range of diagnostic criteria that distinguish Alzheimer’s disease (AD) from other mental health-related disorders. Depression presents in a very similar pattern to early stages of AD. Therefore, the neuropsychological evaluation will rule in or out diagnostic criteria and pinpoint which medication should be recommended. A collaborative approach between psychologists, physicians, and caretakers is crucial in obtaining an accurate diagnosis to develop an appropriate treatment plan. Results from the neuropsychological assessment provide physicians with information to develop a medication regimen that helps treat a patient’s cognitive and behavioral symptoms. Additionally, this information provides caretakers with psychoeducation to help understand the current functioning of their loved ones. The neuropsychological test findings coupled with a medical intervention is imperative to help patients and their families to develop adaptive methods that may help minimize the difficulties of daily living.</p> Anna Maria Jadwiga Wegierek Katarzyna Lesniak Shan Patel Yuliya Bogdanovskaya Copyright (c) 2019 Anna Maria Jadwiga Wegierek, Katarzyna Lesniak, Shan Patel, Yuliya Bogdanovskaya https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 237 250 10.15586/alzheimersdisease.2019.ch15 Index https://exonpublications.com/index.php/exon/article/view/248 Index Copyright (c) 2019 https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 251 255 10.15586/alzheimersdisease.2019.ind About the Editor https://exonpublications.com/index.php/exon/article/view/249 <p><img src="/public/site/images/cmorais/TW_head_2019_1501.jpg"></p> <p>Thomas Wisniewski, MD, is Professor of Neurology, Pathology and Psychiatry at New York University School of Medicine (NYUSM). He is also the Director of the NYUSM Alzheimer’s Disease Center, the Conformational Disorders Laboratory, the Center for Cognitive Neurology, the Barlow Memory Disorders Center, and the Division of Aging and Dementia. His group helped develop novel therapeutic approaches to Alzheimer’s disease (AD), in particular, immunotherapeutic approaches. His laboratory developed both active and passive immunizations, specifically targeting abnormal oligomeric protein conformation, as well as a means to stimulate innate immunity to ameliorate AD pathology. Recently, he developed an unbiased proteomic methodology that produces robust data utilizing archival formalin, fixed paraffin-embedded human tissue, and used this method to perform the most extensive proteomic analysis of amyloid plaques. In addition, Dr. Wisniewski was the first to hypothesize that apolipoprotein (apo) E plays a critical role in AD pathogenesis, coining the term “pathological chaperone” for the role of apoE in AD. More recently, his laboratory developed a novel therapeutic approach based on blocking the interactions between apoE and amyloid β, showing it to be effective in multiple AD models. This work has led to more than 300 peer-reviewed publications and over 25 issued patents.</p> Thomas Wisniewski, MD Copyright (c) 2019 https://creativecommons.org/licenses/by-nc/4.0 2019-11-21 2019-11-21 10.15586/alzheimersdisease.2019.editor