Human Biochemistry

By Gerald Litwack

Human Biochemistry includes clinical case studies and applications that are useful to medical, dentistry and pharmacy students. It enables users to practice for future careers as both clinicians and researchers.

Offering immediate application of biochemical principles into clinical terms in an updated way, this book is the unparalleled textbook for medical biochemistry courses in medical, dental and pharmacy programs.

• Winner of a 2018 Most Promising New Textbook (College) Award (Texty) from the Textbook and Academic Authors Association
• 2019 PROSE Awards - Winner: Category: Textbook/Biological and Life Science: Association of American Publishers
• Offers immediate application of biochemical principles into clinical terms in an updated way
• Contains coverage of the most current research in medical biochemistry
• Presents the first solution designed to reflect the needs of both research oriented and clinically oriented medical students

• Language: English
• Publisher: Academic Press
• Release date: Nov 9, 2017
• ISBN: 9780123838650

Gerald Litwack

Dr. Litwack has authored 3 textbooks on biochemistry and hormones (one with John Wiley & Sons and 2 with Academic Press/Elsevier) and he has edited more than 70 volumes in the Vitamins & Hormones series (Academic Press/Elsevier); he has edited 14 volumes entitled Biochemical Actions of Hormones (Academica Press); He has edited (with David Kritchevsky) Actions of Hormones on Molecular Processes (Academic Press)

Book preview

Human Biochemistry

Gerald Litwack, Ph.D.

Los Angeles, CA, United States

Table of Contents

Cover image

Title page

Copyright

Dedication

Preface

Introduction

Chapter 1. Organ Systems and Tissues

Abstract

Treatment of the Injured Knee: Use of Stem Cells to Replace Damaged Cartilage

Development of Organs

Stem Cells

Gross Structures and Functions of Organ Systems

Skin

The Skeleton

Cellular Composition of Tissues

Summary

Suggested Reading

Chapter 2. The Cell

Abstract

Cellular Trafficking in Alzheimer’s Disease

Cell Membrane

Nucleus and Cell Division

Cytoplasm and Cytoskeleton

Endoplasmic Reticulum

Golgi Apparatus

Mitochondria

Peroxisome

Lysosome

Summary

Suggested Reading

Chapter 3. Introductory Discussion on Water, pH, Buffers and General Features of Receptors, Channels and Pumps

Abstract

Diabetes Insipidus

Thirst and Arginine Vasopressin (AVP)

Action of Arginine Vasopressin on the Distal Kidney Tubule

Water and Biological Roles

Water Channels: Aquaporins (AQPs)

The Role of Water in Protein Folding

Protein–Water Interactions in Enzymatic Reactions

Metabolic Water

Proton Transfer in Liquid Water

The Concentration of Hydrogen Ions (Protons) in Solution (pH)

Buffers

Receptors

Ion Channels

Enzymatic Pumping Mechanism

Summary

Suggested Reading

Chapter 4. Proteins

Abstract

Prion Disease, A Disease of Protein Conformational Change

Amino Acids

Proteins

Protein Classification

Summary

Suggested Reading

Chapter 5. Enzymes

Abstract

Diagnostic Enzymology

General Aspects of Catalysis

Classification

Coenzymes

Prosthetic Groups

Drugs That Operate as Enzyme Inhibitors

Enzyme Replacement Therapy—Gaucher Disease

Summary

Suggested Reading

Chapter 6. Insulin and Sugars

Abstract

Diabetes

Insulin

The Pancreatic β-Cell and Insulin Secretion

Detrimental Effects of Diabetes

Synthetic Sweeteners

Chemistry of Simple Sugars

Glucose Transport

Pentose Phosphate Pathway

Conversion of Ribose to Deoxyribose

Carbohydrate Constituents of Proteins—Glycoproteins

Transfer of Nucleotide Sugars into the Golgi cisternae

Sugars in Blood Group Proteins

Lactose Intolerance

Glycobiology

Summary

Suggested Reading

Chapter 7. Glycogen and Glycogenolysis

Abstract

Glycogen Storage Disease (GSD) Type I, von Gierke Disease (and Others: At Least 11 Types of GSD)

Glycogen—The Storage Carbohydrate

Glucose Metabolism in Muscle

Glycogenin and Formation of Glycogen

Glycogenolysis (Releasing Glucose from Glycogen)

Hormonal Control of Glycogen Metabolism and Blood Glucose Level

Glucagon

Epinephrine

Insulin

Glycogen Phosphorylase

Different Glucose Transporters (GLUTs) in Different Tissues

Summary

Suggested Reading

Chapter 8. Glycolysis and Gluconeogenesis

Abstract

Hemolytic Anemia: Glyceraldehyde-3-Phosphate Dehydrogenase (G3PDH) Deficiency (A Rare Disease)

The Pentose Phosphate Pathway (PPP)

Glycolysis, the Emden–Meyerhof Pathway

Phosphofructokinase Enzymes Involved in the Conversion of Fructose-6-Phosphate to Fructose-1,6-Bisphosphate

Cell Proliferation and Tumor Growth—the Warburg Effect

Gluconeogenesis

Glucose Transporters

Summary

Suggested Reading

Chapter 9. Lipids

Abstract

Hypercholesterolemia

Biosynthesis of Cholesterol

Inhibition of Liver HMGCoA Reductase by Drugs (Statins)

The ARH Protein

Bile Acids

Fatty Acids and Fat

Properties of Lipoproteins

Lipid Anchoring of Proteins to Membranes

Summary

Suggested Reading

Chapter 10. Nucleic Acids and Molecular Genetics

Abstract

Huntington’s Disease, a Single Gene Mutation

Purines and Pyrimidines

Base Pairing

The Structure of DNA

Biosynthesis of Purines and Pyrimidines

Purine Interconversions

Catabolism of Purine and Pyrimidine Nucleotides

Salvage Pathway

Mitochondrial DNA Synthesis

DNA Mutations and Damage

Restriction Enzymes

Probing Libraries for Specific Genes

Hybridization Techniques

Amplification of DNA Sequences: Polymerase Chain Reaction

Identification of a Specific Gene on a Chromosome

Determining DNA Sequence

Inhibitors of DNA Synthesis

RNA Interference

Coding DNA

Noncoding DNA

Transposons

Alu Elements

5′ Capping of RNA Containing Exons and Introns

Polyadenylation of Pre-mRNA

Overall Transcription–Translation Process

Intron Exclusion From Pre-mRNA

Coding Ribonucleic Acid (RNA)

Noncoding RNAs

Ribosomal RNA (rRNA)

Small Nucleolar RNA (snoRNA)

Genomics

Summary

Suggested Reading

Chapter 11. Protein Biosynthesis

Abstract

Defects in Mitochondrial Oxidative Phosphorylation and Disease; Deficiency in Mitochondrial Translation

Protein Synthesis Directed by the Nucleus

The Ribosome

Summary

Suggested Reading

Chapter 12. Transcription

Abstract

Congenital Heart Disease; Mutations of Transcription Factors

Transcription Factors and the Transcription Complex

Enhancers

Coactivators and Corepressors

The Glucocorticoid Receptor as a Model Transcription Factor

Classes of Nuclear Receptors

Cell Membrane Receptors

Receptor Isoforms

Chromatin

Summary

Suggested Reading

Chapter 13. Metabolism of Amino Acids

Abstract

Urea-Cycle-Related Disease: Hyperammonemia

The Urea Cycle

Amino Acid Metabolism: Amino and Amide Group Transfers

Transamination

Transamidation

Deamination

Oxidation of Amino Acids

Amino Acid Racemization

L-Amino Acid Decarboxylation

Metabolism of Amino Acids to Active Substances

Catabolism of Amino Acids

Summary

Suggested Reading

Chapter 14. Metabolism of Fat, Carbohydrate, and Nucleic Acids

Abstract

Gaucher Disease: Most Common Lipid Storage Disease

Lipid Metabolism

Carbohydrate Metabolism

The Tricarboxylic Acid Cycle (TCA Cycle), Citric Acid Cycle, or Kreb’s Cycle

Nucleic Acid Metabolism

Overview of Metabolism

Metabolism in Stem Cells

Summary

Suggested Reading

Chapter 15. Polypeptide Hormones

Abstract

Panhypopituitarism: Malfunction of the Hypothalamus–Pituitary-End Organ Axis

Hormonal Signaling Pathways

Signaling From Hypothalamus to Posterior Pituitary

Models of Hormone Action of Anterior Pituitary Hormones

Orexins (Hypocretins): Hypothalamic Hormones Controlling Sleep and Feeding

Adiponectin From Adipose (Fat) Tissue

Hormones of the Gastrointestinal (GI) Tract

Summary

Suggested Reading

Chapter 16. Steroid Hormones

Abstract

Stress

Structures of Steroid Hormone Receptors

Physiological Functions of Steroid Hormones from Specific Receptor Knockouts

Steroid Transporting Proteins in Plasma

Enzymatic Inactivation of Cortisol

Cortisol and Aldosterone

Dehydroepiandrosterone (DHEA)

Structural Considerations of Steroid Hormones

Receptor Activation

Vitamin D Hormone

Thyroid Hormone

Environmental Xenobiotics That Agonize or Antagonize the Estrogen Receptor

Crosstalk Between Steroid Receptors and Peptide Hormones

Sex Hormones

Peroxisome Proliferators and Their Receptors

Glucocorticoid Induction of Programmed Cell Death (Apoptosis)

Summary

Suggested Reading

Chapter 17. Growth Factors and Cytokines

Abstract

Prospects for Cytokine TRAIL (TNF-Related Apoptosis Inducing Ligand) and Ovarian Cancer

The Tumor Necrosis Factor (TNF) Superfamily

Growth Factors

Summary

Suggested Reading

Chapter 18. Membrane Transport

Abstract

Cystic Fibrosis (Mucoviscidosis) and Aberrant Ion Transport

Types of Membrane Transport

Fatty Acid Transport Proteins

Voltage-Gated Sodium Channels

Epithelial Sodium Conductance Channel

Mutidrug Resistance Channel (MDR), a Member of the ABC Transporter Superfamily

Blood–Brain-Barrier

Summary

Suggested Reading

Chapter 19. Micronutrients (Metals and Iodine)

Abstract

Iron Deficiency Anemia

Uptake of Iron During Digestion

Heme Synthesis

Hemoglobin Formation

Trace Elements

Summary

Suggested reading

Chapter 20. Vitamins and Nutrition

Abstract

Vitamin D Deficiency

Vitamins

Fat-Soluble Vitamins

Balanced Nutrition

Summary

Suggested Reading

Chapter 21. Blood and Lymphatic System

Abstract

Deep Vein Thrombosis

Blood-Clotting Mechanism

Blood

Lymphatic System

Summary

Suggested Reading

List of Abbreviations

Appendix 1. Abbreviations of the Common Amino Acids

Appendix 2. The Genetic Code

Appendix 3. Weights and Measures

Index

Copyright

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Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

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ISBN: 978-0-12-383864-3

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Dedication

For my family, especially for the younger ones: Kate, Geoff, Suzie and Deb.

Preface

Gerald Litwack, PhD, Los Angeles, CA, United States

This book is designed for senior undergraduates, graduate students, and, especially, medical students. It should also be useful for teachers, researchers, and clinicians for designing lectures and as a desk reference. Although the book has considerable depth, the instructor can make use of various illustrations in the book to present a course at the level he/she wishes. The more extensive information can be gained by the interested student and the list of references following each chapter will be useful for further individual research.

Many medical students question the reason that they have to study biochemistry when their focus is thought to be exclusively on medicine. They often ask: Why do I have to learn biochemistry? In this volume, each chapter opens with a disease or clinical condition that is presented in clinical terms and subsequently dissected to the molecular biochemical level, demonstrating the principles of the chapter. This approach explains the basis of the disease and frequently discusses diagnosis and treatment, cementing the relationship of biochemistry to medicine and disease. Thus the question of relevance is answered.

Undergraduate and graduate students often have little exposure to medicine and disease. Human Biochemistry should serve to introduce these students to clinical examples in molecular terms that will broaden their education.

A clinically related example at the beginning of each chapter was first employed in Human Biochemistry & Disease by myself, published in 2008. Human Biochemistry presents many modifications. In particular, the only three-dimensional X-ray structures of molecules used here are those conveying some property or activity that is obvious to the reader. The figures used here all have been redrawn with a consistent font and white or very light backgrounds. Most figures are in color. As further teaching aids, many figures are converted to slides and other teaching aids by Academic Press/Elsevier, available to the instructor. Multiple-choice questions at the end of each chapter emphasize the principles of the chapter and prepare the student for future examinations.

The first three chapters are introductory. The first review chapter deals with the gross anatomy of the major organs in the human body, less important for the medical student if he/she is taking a class in gross anatomy concurrently with a course in biochemistry. However, this review may well be useful for nonmedical students. The first two chapters end with a summary, suggested reading list involving journal papers and books, and multiple-choice review questions. The third chapter and all the subsequent chapters close with a summary, suggested reading list, multiple-choice review questions, and a case-based problem. The case-based problem is most effectively used in small group teaching where a clinician and scientist lead the discussion. The objective of the case-based problem is to, step-by-step, reach a diagnosis and treatment.

Early on, Janice Audet of Elsevier, now at Harvard University Press, aided my work. Subsequently, Fenton Coulthurst of Elsevier, Oxford, United Kingdom, was instrumental in the progress and publication of the book.

Introduction

Gerald Litwack

Enough is known at present about the biochemistry of disease to securely link this science to medicine. Biochemistry and physiology are foundations of medicine. Pharmacology, the practice of which generates medicines, can be defined as the biochemistry of drug action. As most medical students, who encounter biochemistry, cell biology, molecular biology, and genetics in the first year of medical school, thirst for training and experience in medicine, it behooves instructors of biochemistry in this setting to establish firmly the interconnection between biochemistry and disease. Otherwise, students tend to separate this science from medicine and often wonder why they are taking a course that would seem remote from medicine and disease. This book, which introduces the basics of biochemistry, emphasizes the connection between biochemistry and disease so that the student is aware of the basic information supporting our current knowledge. Accordingly, relevant diseases are introduced in each chapter that relate to the principles explored in the chapter and extend the understanding of the disease often to the level of molecules.

The biochemical information is up to date. At the end of each chapter, a summary appears. In addition, each chapter has supporting online materials, including a set of review questions in the form of USLME (United States Medical Licensing Examination) examinations serving to familiarize the student with this type of testing. These questions cover the major points of the chapter and emphasize the central principles. Furthermore, the online support supplements each chapter with a case presentation that would incorporate the principles of the chapter in a clinical context. This is becoming a favored mechanism for the deductive diagnosis of a set of symptoms by a small group under the direction of a mentor. The experiential nature of this exercise serves to incorporate basic information into the thinking of the student so that he/she may retain useful information for a long period compared to rote memorization, recapitulation during testing and forgetting the information after the test is over. This technique facilitates the capability of a student to solve problems and introduces the technology for gathering relevant information, a prescription for the lifelong learner.

In all, this book contains 19 chapters that cover the essential information in a basic course in medical biochemistry. Importantly, the stress is on the integration of biochemistry, disease and medicine. The chapters are ordered so that a discussion of proteins and enzymes comes first. In my view, all succeeding information depends upon knowledge of enzymes that allow chemical reactions to occur under bodily conditions. I realize that all instructors may not agree with this order and might prefer to introduce the subject of nucleic acids at the outset. In that case, one can begin with Chapter 8, Glycolysis and Gluconeogenesis, leaving Chapters 4 and 5 for later introduction.

There are many figures in this book. They are used to provide pathways and overall views of mechanisms of action. There are some figures showing three-dimensional structures. These are used only when they shed light upon a mechanism or interaction of a macromolecule with a ligand, to show protein–protein interactions or to graphically demonstrate an enzymatic action. The use of such figures is limited to increasing the understanding of a particular mechanism.

Clinical case-based exercises are developed by individuals familiar with this technique. Likewise, the USMLE type questions are developed by separate experts. General references are included for further reading at the end of each chapter.

The first three chapters are introductory. In Chapter 1, Organ Systems and Tissues are discussed the organ systems and tissues, including aspects of tissue development. Chapter 2, The Cell focuses down to the cell and its composition with particular reference to organelles and subcellular particles. In Chapter 3, Water, pH, Buffers and Introduction to the General Features of Receptors, Channels, and Pumps, there is a discussion of water, pH, buffer systems, and general features of receptors and channels. These are basic concepts that a student should learn at the outset. The chapters introduce physiology and cell biology as larger contexts of biochemistry which focuses on molecules but has become miscible with cell—and molecular—biology.

At the end of the book is a Glossary, explaining specific names and abbreviations, an in depth index and Appendices giving the names of amino acids, their abbreviations, and some characteristics, the genetic code, and weights and measures.

Studying the basic information in this book should provide a format for lectures, if they are used, and as well a source of information for small group study and reference during the exercise of case- or problem-based learning.

Chapter 1

Organ Systems and Tissues

Abstract

This is an introductory chapter featuring the gross anatomy of the major organs of the human body. As for all the chapters, this one begins with a medical condition highlighting the use of stem cells therapeutically. Topics covered include: development of organs, stem cells, discussion of the major organs and terminates with a summary, suggested reading, and multiple-choice review questions.

Keywords

Gastrula; endoderm; ectoderm; skin; skeletal system; muscle; circulatory system; digestive system; central nervous system; peripheral nervous system; respiratory system; digestive system; excretory system; tissue cells; fertilization

Treatment of the Injured Knee: Use of Stem Cells to Replace Damaged Cartilage

In the human the knee, as it supports the entire body weight is susceptible, not only to acute injury, but, in particular, to the development of chronic osteoarthritis. Osteoarthritis can be defined as the degeneration of joint cartilage and the bone beneath it and it occurs in any joint, especially middle age and older, in the hip, knee, and thumb. The most common type of osteoarthritis is in the knee and leads to the deterioration of the articular cartilage. The articular cartilage is that which covers the bone and the hyaline cartilage is located within the joints. Arthroscopic surgery has been most widely used to treat this condition but with the advent of new research on stem cells, this condition is being ameliorated without surgery by the injection of stem cells into the site. Normal and osteoarthritic cartilage is shown in Fig. 1.1.

Figure 1.1 Macroscopic signs of osteoarthritis knee hyaline cartilage. (A) Healthy cartilage. (B) Osteoarthritis cartilage. Reproduced from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017310/figure/F1/.

Under the microscope healthy and osteoarthritic knee hyaline cartilage can be differentiated as shown in Fig. 1.2.

Figure 1.2 Microscopic signs: (A) microscopic signs of healthy knee hyaline cartilage. The histological (HE, hemotoxylin-eosin staining) analysis of cartilage form normal donor showed a preserved morphological structure with no sign of cartilage degradation. Moreover, the surface of healthy hyaline cartilage appears white, shiny, elastic, and firm. Magnification 20×; scale bars: 100 μm. (B) Microscopic signs of osteoarthritis (OA) knee hyaline cartilage. The histological staining (HE staining) analysis of cartilage from OA donor. The donor demonstrated joint swelling and edema, horizontal cleavage tears or flaps, the surface became dull and irregular and had minimal healing capacity. Magnification 20×; scale bars: 100 μm. Moderate OA cartilage (black arrow); the structural alterations included a reduction of cartilage thickness of the superficial and middle zones. The structure of the collagen network is damaged, which leads to reduced thickness of the cartilage. The chondrocytes are unable to maintain their repair activity with subsequent loss of the cartilage tissue. Severe OA cartilage (blue arrow), demonstrated deep surface clefts, disappearance of cells from the tangential zone, cloning, and a lack of cells in the intermediate and radial zone, which are not arranged in columns. The tidemark is no longer intact and the subchondrial bone shows fibrillation. Reproduced from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017310/figure/F2/.

The zones of the articular cartilage down to the bone, including the tidemark, is shown in Fig. 1.3.

Figure 1.3 The articular (hyaline) cartilage. The articular cartilage is one of five forms of cartilage: the hyaline or articular cartilage, the fibroblastic cartilage comprising the meniscus, the fibrocartilage located at the tendon and the ligament insertion into bone, the elastic cartilage of the trachea and the physeal cartilage of the growth plate (physeal, area of bone separating metaphysis and epiphysis where cartilage grows). Reproduced from: http://www.orthobullets.com/basic-science/9017/articular-cartilage.

In attempting to repair cartilage of an osteoarthritic knee, chondrocytes are extracted arthroscopically from normal cartilage in the nonload-bearing intercondylar notch or the upper ridge of femoral condyles. These cells are then grown in tissue culture for 4–6 weeks (Fig. 1.4) under conditions where no contamination of any sort can take place (good practices). When sufficient numbers of cells have grown up, they are injected into the damaged area, usually in combination with a matrix structure (Fig. 1.5).

Figure 1.4 Development of mesenchymal stem cells. (A) First day of culture; (B) 3rd day of culture; (C) 1 week of culture. Magnification 40×; scale bars: 50 μm. Reproduced from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017310/figure/F4/.

Figure 1.5 Graphic representation of cartilage tissue engineering. Staring with X in upper center, chondrocytes, or mesenchymal stem cells are removed from healthy cartilage; the mesenchymal stem cells are isolated and cultured in tissue culture media for about 7 days under strict conditions so that no impurities can contaminate the culture. The cells are concentrated by centrifugation, combined with a matrix substance and various growth factors and injected back into the damaged knee (V). The damaged knee, by itself, cannot produce enough stem cells to repair the damage. Reproduced from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017310/figure/F3/.

The implanted cells, provided with growth factors grow in the native environment and form new cartilage tissue. In most cases, there is a definite improvement in which there is a reduction of pain and increased ability to use the affected knee, even in competitive sports. While this sort of success in treatment of knee cartilage problems has been reported in several clinical trials there is, as yet, no uniform consensus on the effectiveness of this procedure, indicating the need for further clinical trials. This clinical example serves to highlight some of the features of this chapter, particularly with reference to development in which certain layers of cells are equivalent to stem cells that can, under the appropriate conditions, develop into any tissue in the body.

Development of Organs

Development begins with fertilization of the ovum by a sperm. The early embryo undergoes a cell division generating the two-cell stage, each daughter cell containing the genome of both parents. The division is of a cleavage type (without cell growth) indicating that the size of the cells becomes progressively smaller with each division. Within 5 days cell division continues through the four-cell stage, the eight-cell stage and the sixteen-cell stage, the morula (by Day 3) and forming the blastocyst which contains an outer and inner cell mass. At the 16-cell stage, there are eight large cells outside and eight smaller cells inside the structure. By the 5th day the trophoblast is distinguishable with a large blastocyst cavity (the blastocoel) and a distinct inner and outer cell mass. By Day 7 the blastocyst becomes enlarged. This progression is depicted in Fig. 1.6.

Figure 1.6 The stages of early human development. Reproduced from: http://openlearn.open.ac.uk/file.php/1638/formats/print.htm.

Stem Cells

Cells of the blastocyst can form all the tissues of all the organs in the body. The only cells that are totipotent (can develop into every cell type in the body including placental cells) are the embryonic (stem) cells existing after the first and second cell divisions following fertilization. Similar in potency are pluripotent stem cells (embryonic stem cells capable of generating all cell types in the body) derived from the inner cell mass of the blastocyst. These cells, in the appropriate environment, can differentiate into every cell type present in the organism. What is more, this differentiation can take place either in vivo or in vitro. Stem cells also can be obtained from adults (generally multipotent stem cells that can develop into more than one cell type) as most tissues in the body have stores of stem cells (caches) that are used to replace the cells in the tissue that have died. Some caches are more plentiful than others and a great deal of research has centered on the stem cells in caches stored in joints (mesenchymal stem cells), for example. Adult stem cells, in addition to embryonic stem cells, can be transformed into many types of tissue cells under the appropriate environmental conditions. The various stem cells and tissue progenitor cells have different properties reflected in differences in their metabolism as listed in Table 1.1.

Table 1.1

Summary of Metabolism in Respective Stem and Progenitor Cells

OxPhos, oxidative phosphorylation; PPP, pentose phosphate pathway; ROS, reactive oxygen species.

Source: Reproduced from: Shyh-Chang, N., Daley, G.Q., Cantley, L.C., 2013. Stem cell metabolism in tissue development and aging. Development, 140, 2535–2547.

Mesenchymal stem cells have been proliferated in vitro and subsequently used to regenerate cartilage in knee joints that have suffered degeneration, for example. Many such clinical interventions, however, may not be permanent and the process has to be repeated after a time. There is some concern that stem cells injected into patients could generate into cancer cells although the evidence that this is an inherent danger in using them for clinical treatments, so far, has not borne out. Since each tissue in the body may have a cache of stem cells, the aging process could be the result of insufficient stem cells to replace tissue cells that become damaged and die out. Consequently the generation of such stem cells in vitro constitutes the practice and hope for further clinical treatments to replace tissue cells and organs. Stem cells generated in vitro must be safe from any contaminating substances or organisms and all are generated under good manufacturing practices (GMP) promulgated by the FDA (Food and Drug Administration). A newer development under the heading of therapeutic cloning involves the use of pluripotent stem cells (without destruction of a human embryo) that are genetically identical to the donor to produce pluripotent stem cells that can be used to treat disease. In this case, adult skin cells from a donor can be used to extract his/her DNA and this DNA can be fused electrically with donated adult human eggs whose DNA has been removed. The resulting embryo at the level of the blastocyst is the source of pluripotent stem cells. The resulting pluripotent cells should be useful in treating many human diseases, including Parkinson’s disease, type 1 diabetes, heart disease, and others.

The next stage from the blastula is the gastrula developed by the invasion (invagination) of the bottom layer of cells of the blastula up into the blastocoel forming two layers with a pore (blastopore) on the bottom where the invasion began as shown in Fig. 1.7. Now, two germ layers are determined, the outer layer of ectoderm and the inner layer of endoderm.

Figure 1.7 Formation of the gastrula from the blastula. Reproduced from: http://chsweb.lr.k12.nj.us/mstanley/outlines/animals/antax/image51.gif.

Further development reveals the internal mesoderm as shown in Fig. 1.8.

Figure 1.8 Further development of the gastrula. Reproduced from: http://www.carolguze.com/images/embryos/gastrulation.jpg.

These three layers of cells: the ectoderm, endoderm, and mesoderm lead to the development of specific tissues and organs. From the endoderm is derived the primitive gut that, in turn, generates the lungs, liver, pancreas, and digestive tubes. The ectoderm leads to the development of the epidermis, the forerunner of the skin, hair, and mammary glands. It also leads to the epidermal placodes and then to the lens of the eye and the inner ear. Placodes are thickenings of the ectoderm. Apparently, there are a number of different groups of placodes but they all have a similar developmental history and they lead to different aspects of the nervous system. Importantly, the ectoderm is the precursor of the neural tubes and neural tissue leading to the development of the brain and spinal cord (central nervous system, CNS) and the peripheral nervous system (PNS). The mesoderm gives rise to the axial skeleton (bones of the head and trunk), skeletal muscle as well as the connective tissue of the skin. It also gives rise to other organs: the oviducts and uterus, kidney, ovary, and testes, the connective tissue of the body wall and limbs, the mesenteries, heart, and blood vessels. The endoderm is the precursor for the remaining bodily systems. The summary of the further development of these three embryonic layers of cells is shown in Fig. 1.9.

Figure 1.9 Summary of the three embryonic layers of cells and their fates in the human body. Reproduced from: http://www.unige.ch/cyberdocuments/theses2004/HeQ/images/Fig.3C.jpg.

Gross Structures and Functions of Organ Systems

Most of this information is already obvious to you. However, the organ systems will be described briefly. Organs usually contain more than one type of tissue. Tissues will be discussed in the next section.

Skin

The skin is the largest organ in the body. It is shown in cross-section in Fig. 1.10.

Figure 1.10 Cross-section of the skin. Reproduced from: http://content.revolutionhealth.com/contentimages/n5551176.jpg.

From the outside extending internally, the skin consists of epidermis, dermis and a subcutaneous layer or hypodermis (Fig. 1.10). The three layers are derived from ectoderm. The skin functions in various ways providing insulation, regulation of temperature, and sensation. It is the site of the synthesis of vitamin D (cholecalciferol) from 7-dehydrocholesterol. 7-Dehydrocholesterol must be activated in cells of the skin by the UV radiation in sunlight in order for it to proceed to form the active form of vitamin D in the body via liver and kidney enzymes. Theoretically, exposure to sunlight for 10 min each day would satisfy the requirement for vitamin D. Vitamin D is considered as a vitamin because the content in the body is inadequate and it must be made available through the effect of sunlight and vitamin D in foods. The activated form of vitamin D in the body acts like a steroid hormone. Cholecalciferol must undergo further hydroxylations in the body to be generated as the active hormonal form, as will be discussed in the chapter on steroid hormones, because the active form of vitamin D is a ligand for the vitamin D receptor, a member of the steroid nuclear gene family.

Pigmentation of the skin is due to melanin and the extent of pigmentation varies among populations. Skin color is controlled by genes and by the environment. In hotter environments the body hair is decreased along with an increase in sweat glands to cool the body through evaporation of perspiration. Strong sunlight can cause skin damage and destroy folic acid and also can lead to basal cell carcinoma and sometimes to melanoma. Humans living in these environments have increased melanin that protects against damaging radiation from sunlight. On the other hand, humans living in colder and darker climates have lighter skin to optimize the penetration of UV sunlight for the production of vitamin D. Children who are raised in a dark environment with a small number of sunny days can develop colon cancer in adulthood, owing to a deficiency in this vitamin. Vitamin D is known for its beneficial effects on the immune surveillance system. However, in certain regions, such as Alaska, the natives have dark skin in the face of a cold and dark environment. In this case the diet of these natives is very rich in vitamin D and the skin pigmentation protects them against the strong radiation reflected from surrounding ice and snow. Skin pigmentation is under genetic control and involves the regulation of genes involved in the synthesis of melanin and other factors. For example, stress can affect skin color because products of the activated gene for proopiomelanocortin include ACTH and melanocyte stimulating hormone that stimulate the formation and release of cortisol and the formation of melanin. Also, the skin is the site of as many as one thousand species of bacteria. Many of the mechanisms involved are discussed in later chapters.

The Skeleton

The skeletal system is shown in Fig. 1.11. The major bones are labeled in the figure and there are 206 bones in the mature human skeleton. There are many more separate bones in early development but there are fusions in the growing child. The thigh bone (femur) is the longest bone in the body and the smallest bone resides in the inner ear (stirrup). Males have longer legs and arms than females and females have a wider pelvis. Importantly, bones are the sites of manufacture of blood cells and the storage sites for minerals. Calcium is a major component of the bone structure. Associated organs are tendons, ligaments, and cartilage.

Figure 1.11 Gross structure of the human skeleton. Reproduced from: http://www.enchantedlearning.com/subjects/anatomy/skeleton/Skelprintout.shtml.

The muscle system is shown in Fig. 1.12. The more than six hundred skeletal muscles (striated muscle) attach to bones and connect to joints. Muscles can work in pairs for motion and also control the movement of substances through some organs (circulation, heart, stomach, and intestines). There are also smooth muscles that are involuntary and are responsible for the contraction of hollow organs, such as the gastrointestinal tract, blood vessels, airways, bladder, and uterus. The other muscle type is the striated muscle, a voluntary muscle that is connected to bone at one or both ends. It has dark and light bands with repeating sarcomeres (the basic mechanical unit of muscle consisting of thin filaments each of which contains two strands of actin, a single strand of a regulatory protein and two thick filaments of myosin).

Figure 1.12 The human body muscle diagram. Reproduced from: http://www.human-body-facts.com/human-body-muscle-diagram.html.

The circulatory system transports oxygen and CO2, nutrients, hormones, and waste products throughout the body. It involves the heart, blood vessels, and blood. A diagram of the circulatory system is shown in Fig. 1.13.

Figure 1.13 Diagram of the circulatory system. Reproduced from: http://image.tutorvista.com/content/circulation-animals/human-blood-circulatory-system.jpeg.

The nervous system is made up of the central nervous system (CNS) and the peripheral nervous system (PNS). The function of the nervous system is to send electrical signals throughout the body that direct movement and behavior. It is a major part of the control of physiological processes including the circulation and digestion. The central nervous system consists of the brain and spinal column; the rest are peripheral nerves. A diagram of the nervous system is shown in Fig. 1.14.

Figure 1.14 The human nervous system. The PNS is in blue and the CNS is in red. Reproduced from: http://www.nationmaster.com/encyclopedia/Peripheral-nervous-system.

The respiratory system consists of the nose, trachea, and lungs as shown in Fig. 1.15. Oxygen is taken in from the outside atmosphere and CO2 is expelled. This system exchanges oxygen and CO2 between the blood and the organs.

Figure 1.15 Organs of the respiratory system. Reproduced from: http://www.byronsmith.ca/everest2000/gfx/ehb_respiratorysystem.gif.

The digestive system consists of the mouth, esophagus, stomach, small intestine, and large intestine. The liver produces detergents and the pancreas produces digestive enzymes and both are transported to the intestine for digestion. The overall functions are to take in nutrients, break them down in the intestinal tract and absorb the products into the bodily circulation. The transport mechanisms for moving the products of food digestion into the bloodstream and the tissues are presented in later chapters. A diagram of the digestive system is shown in Fig. 1.16.

Figure 1.16 Diagram of the digestive system. Reproduced from: http://eatwellgetwell.files.wordpress.com/2006/05/digestion_good2.jpg.

There are many glands in the body that secrete hormones. The hypothalamus, pituitary (anterior, posterior, and cells of the intermediate pituitary), thyroid, pancreas, and adrenals are some of the major glands in the endocrine system. Hormones are chemical messages acting on organs distant from the secreting gland that control many functions at the cellular level. Hormones activate their signals through specific receptors. Fig. 1.17 shows glands that constitute the endocrine system.

Figure 1.17 Diagram showing major glands that constitute the endocrine system. Reproduced from: http://cwx.prenhall.com/bookbind/pubbooks/morris5/medialib/images/F02_17.jpg.

In a stress situation, for example, many endocrine glands come into play. A stress event in the outside (the body) environment is filtered through a mechanism in the brain and the appropriate cells in the hypothalamus are signaled to secrete the corticotropin releasing hormone (CRH). This hormone is secreted into a closed portal system connecting the hypothalamus to the pituitary. CRH binds to membrane receptors on one cell type in the anterior pituitary, the corticotrope. This receptor activates a biochemical cascade of signals that result in the secretion of adrenocorticotrophic hormone (ACTH; corticotropin) that enters the general circulation through thin membranes (fenestrations). ACTH circulates in the blood until it reaches its cognate receptor on the membranes of the middle layer of cells in the adrenal cortex. The signaling from the activated ACTH receptor results in the hydrolysis of cholesteryl esters, stored in lipid droplets, to liberate free cholesterol that, with the aid of a specific carrier, enters the mitochondria for the production of corticosteroids (cortisol and some aldosterone) that cross the cell membrane into the general circulation. Cortisol is carried in the circulation by specific proteins but about 10% of the circulating cortisol in is the free form. Unbound cortisol enters virtually every cell in the body and is retained by cells that have the glucocorticoid receptor to which it binds (virtually all cells of the body, except the cells in the space between the posterior pituitary and the anterior pituitary and the hepatobiliary cells, contain some glucocorticoid receptors). If there is more cortisol than there is receptor molecules to bind it, the residual cortisol passes back out of the cell by free diffusion into the bloodstream. In certain tissues, such as the liver and kidney, there are large amounts of the receptor (as many as 50,000 receptor molecules in the liver cell). Not all of these activated receptor molecules are required to generate a transcriptional response. The activated receptors are then carried through the nuclear pore into the cell nucleus (as homodimers) where they interact with many genes that display a specific glucocorticoid responsive element (GRE) resulting in many genes that are transcribed into specific messenger RNAs (or, in some cases, suppressed) and subsequently translated in the cell cytoplasm into specific proteins used metabolically to adapt to stress. Thus after a stress event, virtually every cell type in the body is affected by cortisol (excepting the two cell types mentioned) so that most tissues are changed in their protein populations and the changes in the tissues summate into the bodily adaptation to the stress event. An individual cannot survive without cortisol and its receptor and when this system is somehow damaged (e.g., by trauma to the head, causing a break in the transport system between the hypothalamus and the anterior pituitary) replacement cortisol can be given orally but it is problematic that the patient can predict a major stress event requiring increased doses of the steroid, such as an automobile crash and survival can be threatened by inability to adapt. Cortisol is essential to life. This system is discussed in more detail in the chapter on steroid hormones.

The excretory system filters out toxins, cellular wastes and excess nutrients or water from the circulation. This system includes the kidneys, ureters, bladder, and urethra as shown in Fig. 1.18. An aspect of the kidney in transverse section is also shown.

Figure 1.18 The components of the excretory system. (A) A transverse section of the kidney is shown; (B) the components of the system are shown. Reproduced from: http://sinquefield.com/id6.html.

The reproductive systems of the male and female are diagramed in Fig. 1.19. Part (A) shows the components of the male reproductive system and part (B) shows them for the female.

Figure 1.19 (A) The reproductive system of the human male. (B) The reproductive system of the human female. The g spot has not been proven to be a distinct organ and there is controversial discussion concerning its existence. (A) Reproduced from: http://www.cartage.org.1b/en/themes/Sciences/LifeScience/GeneralBiology/Physiology/ReproductiveSystem/HumanReproduction/malerepro_2.gif. (B) Reproduced from: http://upload.wikimedia.org/wikipedia/commons/7/7a/Female_reproductive_system_lateral.png

The lymphatic system is an elaborate network of lymph nodes with lymph vessels connecting the nodes. As shown in Fig. 1.20 the vessels distribute to every part of the body except the CNS. Important nodes are located in the neck, chest, armpits, abdomen, the pelvis, and the groin. Lymphatic fluid, containing lymphocytes and antibodies (as part of the immune system), flows within the lymph vessels. The nodes act as filters for the removal of bacteria and other unwanted particulate substances.

Figure 1.20 A diagram of the lymphatic system showing the major vessels, nodes, and organs (thymus, spleen, and diaphragm). Reproduced from: http://www.cancervic.org.au/images/CISS/cancer-types/lymphatic.gif.

Cellular Composition of Tissues

There are four main types of cells in tissues. They are epithelial, muscular, connective tissue, and nervous tissue type cells. Also added here are adipose cells and stem cells. These are shown in composite in Fig. 1.21. The complexity of human cell types that constitute variants of the four main types is much greater than suggested by these four major types. There are probably more than two hundred different cell types in the human body.

Figure 1.21 Composite of the major human cell types in tissues. (A) Human tracheal epithelial cells: those pictured are pseudostratified columnar epithelium lining the trachea. The nuclei belong to cells contacting the basement membrane. In this case the epithelial cells are goblet cells (they can alternatively, be ciliated cells). The basal cells regenerate other cell types of the epithelium. (B) Connective tissue of human aorta (ef=elastin fibers). (C) Cardiac muscle cells (cardiomyocytes; labeled as myocytes in the figure). (D) (a) Human smooth muscle, a second type of muscle cell and (b) striated muscle. (E) Human nervous tissue cell. (F) Human adipose tissue. Note the presence of fat globules inside the adipose cells. (G) Human stem cells, pluripotent blastocyst cells. (A) Reproduced from: http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Epithelia/images/trachea041he.jpg. (B) Reproduced from: http://www.austincc.edu/histologyhelp/tissues/images/tn400.jpg. (C) Reproduced from: http://www.medical-look.com/systems_images/Cardiac_Muscle.gif. (D) (a) Reproduced from: http://images.encarta.msn.com/xrefmedia/sharemed/targets/images/pho/t790/T790539A.jpg. (b) Reproduced from: http://images.tutorvista.com/cms/images/123/striated-muscle-fibre.jpeg. (E) Reproduced from: http://images.absoluteastronomy.com/images/encyclopediaimages/g/go/golgistainedpyramidalcell.jpg. (F) Reproduced from: http://biology.nebrwesleyan.edu/courses/Labs/Biology_of_Animals/Images/Lab%20Images/images%20for%20the%20Web/Adipose_Human_400X.jpg. (G) Reproduced from: http://www.sarahwray.com/USERIMAGES/blastocyst.jpg.

Summary

After fertilization of the human egg, there are a series of cell cleavages generating 2 cells, 4 cells, 8 cells, and 16 cells. By Day 3 the morula is formed and the blastocyst. In the next stage the gastrula is formed. At this stage the cells are still pluripotent (stem cells) and two primordial layers, the ectoderm and endoderm are apparent. With further development of the gastrula the internal endoderm is formed. From these three layers of cells, all the tissues and organs of the body are formed. The ectoderm forms mainly nervous tissue, the endoderm forms internal organs through the primitive gut and the mesoderm forms the majority of the internal organs.

The organ systems consist of the skin, skeleton, muscle system, circulation, nervous system (central nervous system and peripheral nervous system), respiratory system, digestive system, endocrine system, excretory system, reproductive systems of the male and female, and the lymphatic system.

The organs are composed of tissues that are represented by four major cell types: epithelial cells, muscle cells (striated and smooth), nervous cells (neurons and others), and connective tissue. In addition, there are adipose cells and stem cells (typified by the cells of the blastocyst). There are more than two hundred variations of cells of the four major types.

Suggested Reading

Literature

1. Berry DC, Stenesen D, Zeve D, Graff JM. The developmental origins of adipose tissue. Development. 2013;140:3939–3949.

2. El-Osta A, Wolffe AP. DNA methylation and histone deacetylation in the control of gene expression: basic biochemistry to human development and disease. Gene Exp. 2000;9:63–75.

3. Fagotto F. The cellular basis of tissue separation. Development. 2014;141:3303–3318.

4. Forster R, et al. Human intestinal tissue with adult stem cell properties derived from pleuripotent stem cells. Stem Cell Rep. 2014;2:838–852.

5. Horie M, et al. Implantation of allogenic synovial stem cells promotes meniscal regeneration in a rabbit meniscal defect model. J Bone Joint Surg Am. 2012;18:701–712.

6. Kenneth KB, et al. Characterization of fetal keratinocytes, showing enhanced stem cell-like properties: a potential source of cells for skin reconstruction. Stem Cell Rep. 2014;3:324–338.

7. Nakamura T, et al. Arthroscopic, histological and MRI analyses of cartilage repair after a minimally invasive method of transplantation of allogenic synovial mesenchymal stromal cells into vartilage defects in pigs. Cytotherapy. 2012;14:327–338.

8. Scheiner ZS, Talib S, Feigal EG. The potential for immunogenicity of autologous induced pleuripotential stem cell-derived therapies. J Biol Chem. 2014;289:4571–4577.

9. Shyh-Chang N, Daley GQ, Cantley LC. Stem cell metabolism in tissue development and aging. Development. 2013;140:2535–2547.

10. Wong KL, et al. Injectable cultured bone marrow-derived mesenchymal stem cells in various knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years’ follow-up. Arthroscopy. 2013;29:2020–2028.

11. Yabut O, Bernstein HS. The promise of human embryonic stem cells in aging-associated diseases. Aging. 2011;3:494–508.

12. Zentner GE, Schacheri PC. The chromatin fingerprint of gene enhancer elements. J Biol Chem. 2012;287:30888–30896.

Books

1. Applegate E. The Anatomy and Physiology Learning System 2nd ed. Philadelphia: W.B. Saunders; 2006.

2. Boron WF, Boulpaep EL. Medical Physiology 2nd ed. Saunders 2009.

3. Koeppen BM, Stanton BA. Berne and Levy, Physiology 6th ed. Amsterdam: Elsevier; 2008.

4. Litwack G, ed. Stem Cell Regulators, volume 87 of Vitamins and Hormones. Amsterdam: Academic Press/Elsevier; 2011.

5. Sherwood L. Human Physiology: From Cells to Systems Belmont, CA: Brooks/Cole; 2008.

Chapter 2

The Cell

Abstract

Another introductory chapter. This chapter focuses on the cell. The chapter opens with a discussion of cellular trafficking in Alzheimer’s disease including a molecular biochemistry approach, characteristic of all clinical discussions in succeeding chapters. Topics covered include functions of the cell membrane, the nucleus and cell division, the cell cycle, the nuclear membrane, the cytoplasm and cytoskeleton, the endoplasmic reticulum, the Golgi apparatus, mitochondria including its genome, the peroxisome, and the lysosome. There is a chapter summary, an extensive reading list, and review multiple-choice questions.

Keywords

Eukaryotic cell; plasma membrane; cholesterol; nucleus; cell division; nucleoli; ribosomal RNA; cell division; checkpoint; nuclear membrane; nuclear pore; cytoplasm; cytoskeleton; endoplasmic reticulum

Cellular Trafficking in Alzheimer’s Disease

According to the Alzheimer’s Association, it is estimated in 2014 that about 5.2 million Americans have Alzheimer’s disease (AD). Of these, about 200,000 are below the age of 65. It is projected that by 2050, unless there is a future effective treatment, there may be about 16 million individuals who are 65 or older who have AD. The annual death rate from AD in the United States is about 500,000. In the year 2014, the estimated cost of AD in the United States is about $214 billion. Because the pathology of AD at the cellular level involves trafficking among different compartments within the affected cell (neuron), AD represents a clinical problem that is illustrative of cellular structure.

Alzheimer's disease, a disease characterized by progressive loss of memory and the loss of cognition (thinking), is related to the excessive degradation by brain secretases (protease enzymes) of the amyloid precursor protein (APP) to amyloid β (Αβ) peptides that are neurotoxic. Thus, a disease can be caused by an endogenous normally functioning protein which, when modified to an abnormal shape, size, or folding, becomes pathologic similar to other neurodegenerative diseases like Prion disease (Creutzfeldt–Jakob disease in the human; see Chapter 4: Proteins). Aggregation and spread of product of a [alpha]-secretase action that damage the brain. This mechanism is pictured in Fig. 2.1.

Figure 2.1 APP structure and metabolism. Schematic representation of APP processing by α-, β-, and γ-secretases. The processing is divided into nonamyloidogenic pathway (left) and the amyloidogenic pathway (right). α- and β-secretases cleave APP in its extracellular domain to release a soluble fragment sAPPα or sAPPβ in the extracellular space and generate carboxy terminal fragments CTFα (83 amino acids long) or CTFβ. These CTFs can subsequently be processed by γ-secretase complex to generate AICD (amyloid precursor protein intracellular domain) and Aβ. Aβ is a small peptide of 39–43 amino acids. Aggregation of Aβ causes amyloidosis, apparently at the root of neurodegenerative disease. The γ-secretase complex is composed of presenilin, nicastrin (NCT), γ-secretase activating protein (GSAP), pen-2, and aph-1. Presenilin, transmembrane protein part of γ-secretase intramembrane protease complex; nicastrin, protein constituent of γ-secretase complex; pen-2, presenilin enhancer of a regulatory protein in γ-secretase complex; aph-1, anterior phalanx-defective protein 1, a subunit of γ-secretase complex. Reproduced from http://journal.frontiersin.org/Journal/10.3389/fphys.2012.00229/full.

Deposition of amyloid (amorphous parenchymal deposits) takes the form of ordered proteinaceous β-sheets (see Chapter 4: Proteins). Amyloid deposition of this type not only occurs in AD, but also occurs in Lewy body (abnormal protein aggregates in neurons) dementia, vascular dementia, and Down’s syndrome, all of which are considered to be age-related neurogenerative diseases.

The amyloid precursor protein (APP) and its breakdown products (CTFs and AICD) are collected in multivesicular bodies within the cell and in secreted exosomes. This trafficking within the cell involves the early endosome that generates multivesicular bodies (multivesicular endosomes) that can either fuse with lysosomes for degradation of the ingredients or be secreted (exosomes) to the extracellular space. Movements of intracellular particles and secretory contents are captured in Fig. 2.2.

Figure 2.2 Amyloid precursor protein (APP) and its metabolites are present in multivesicular bodies (MVBs) and in exosomes. APP and APP-C-terminal fragments (APP-CTFs) are internalized and directed into the internal vesicles of multivesicular bodies (MVBs). At this point APP and its metabolites can either be degraded after the fusion of MVB with lysosomes or can be released in the extracellular space in association with exosomes consecutively to the fusion of MVB with the plasma membrane. APP, Amyloid protein precursor; CTF, C-terminal fragment; AICD, amyloid precursor intracellular domain. Reproduced from http://www.frontiersin.org/Articles/18560/fphys-03-00229-r2/Image.m/fphys-03-00229-g004.jpg.

In the nonamyloidogenic pathway, the intracellular soluble APPα product of a [alpha]-secretase action is not further degraded into products of the actions of β- and γ-secretase that ultimately generate Aβ products leading to their pathological aggregation.

The discovery of a sorting receptor called SORLA reveals that it acts to prevent the amyloid protein precursor from sorting to the late endosomes where the breakdown product, Aβ, is generated and leads to amyloid deposition. Normal SORLA activity insures that the reactions leading to Alzheimer's disease do not occur, whereas the mutations in the gene for SORLA to make the sorting receptor less functional or lower in activity can lead to reactions involving the late endosome and the production of Aβ for amyloid deposition. In Fig. 2.3 are shown the VPS10 (vacuolar protein sorting-10) domain receptors of which one is the SORLA receptor as well as the overall trafficking of SORLA.

Figure 2.3 Structural organization and trafficking path of SORLA. (A) SORLA is a member of the VPS10 domain receptor family, a group of sorting receptors characterized by a VPS10 domain (the name VPS10 derives from the yeast carboxykinase Y sorting receptor [Vps10 protein]). This domain adopts the structure of a large tunnel that is involved in the binding of peptide ligands. In contrast to all other VPS10 domain receptors, SORLA contains complement-type repeats and a β-propeller, structural elements that are found in LRPs (low-density lipoprotein (LDL) receptor-related proteins). The cluster of complement-type repeats is also a site that interacts with ligands. The β-propeller is required for pH-dependent ligands in endosomes. SORLA is produced in the cell as a pro-receptor with a 53 amino acid pro-peptide that folds back on the VPS10 domain to block binding of ligands that target this receptor domain. Cleavage of the pro-peptide by convertases in the TGN (trans-Golgi network) produces the mature receptor, which is able to interact with its target proteins. All known members of the VPS10 domain receptor family are shown to include the yeast receptor VPS10 and the vertebrate proteins sortilin, SORLA, as well as SORCS1, SORCS2, and SORCS3 (SORC, sortilin-related VPS10 domain-containing receptor). For LRPs, the only receptors depicted are those that have been shown to interact with APP. (B) Newly synthesized pro-SORLA is activated in the Golgi by convertase cleavage. From the TGN (transGolgi network), nascent SORLA is directed to the plasma membrane through constitutive secretory vesicles. At the cell surface, some receptor molecules are subject to ectodomain shedding and subsequent intramembrane proteolysis by γ-secretase (γ), resulting in soluble fragments of the extracellular domain and the intracellular tail. Most SORLA molecules at the cell surface remain intact and undergo clathrin-mediated endocytosis. Clathrin is a major protein involved in the formation of coated vesicles. From the early endosomes, internalized receptors, and probably some of their cargo, are returned to the TGN to continue anterograde (forwardly directed) and retrograde shuttling between the secretory and early endosomal compartments. Reproduced from http://jcs.biologists.org/content/126/13/2751/F2.expansion.html.

There are two models for the actions of the sorting receptor SORLA that can take trafficking paths to avoid Alzheimer's disease. In one version, SORLA retains APP in the transGolgi network (TGN) preventing the formation of APP homodimers that are the preferred substrates for secretase. In the other model, SORLA binds APP and shuttles between the TGN and the early endosomes, thus reducing APP from amyloidogenic processing in the endosomes. However, the further processing by the secretases (β and γ) finally avails the aggregatable form, Aβ. These models are shown in Fig. 2.4.

Figure 2.4 Sorting receptor SORLA operates in a trafficking pathway that avoids Alzheimer's disease. (A) Newly synthesized amyloid protein precursor (APP) molecules traverse the Golgi and the transGolgi network (TGN) to the plasma membrane where most precursor molecules are cleaved by α-secretase (α). Nonprocessed precursors internalize from the cell surface through clathrin-mediated endocytosis, which is guided by the interaction between the cytoplasmic tail of APP and the clathrin adapter AP2 (adapter protein 2). From early endosomes, APP moves to the late endosomal–lysosomal compartments or backward to the TGN. Amyloidogenic processing of internalized APP through sequential cleavage by β- and γ-secretases (β, γ) is believed to proceed in endosomes and in the TGN. (B) Internalization of APP is controlled by LRPs (low density lipoprotein [LDL] receptor-related proteins), a group of endocytic receptors expressed in neurons and many other cell types. Fe65 (multidomain adapter protein) mediated association of APP with LRP1 on the cell surface facilitates its endocytic uptake and intracellular processing to Aβ. By contrast, binding to the slow-endocytosing receptors apolipoprotein E receptor 2 (APOER2, also known as LRP8) and LRP1B delays endocytosis but promotes cleavage to sAPPα. Binding of APP to APOER2 is mediated through Fe65 and F-spondin (SPON1; floor plate and thrombospondin homology or VSGP, vascular smooth muscle growth-promoting factor). The mode of interaction between LRP1B and APP might also involve Fe65 or yet unknown adaptors. Reproduced from http://jcs.biologists.org/contents/126/13/2751/F1.expansion.html.

In addition to the deposition of aggregates of Aβ, a second lesion, known as intraneuronal neurofibrillary tangles (NFT), is involved in the development of AD. This lesion is an interneuronal aggregation of microtubule-associated Tau proteins (CNS neuronal protein stabilizers of microtubules) that are abnormally modified. AD progresses by virtue of a synergistic relationship between these two types of lesions (Aβ and NFT). A comparison of a normal vs an Alzheimer neuron is shown in Fig. 2.5.

Figure 2.5 Neuronal degeneration associated with Alzheimer's disease. The figure of the diseased neuron shows β amyloid plaque and neurofibrillary tangles. Reproduced from http://upload.wikimedia.org/wikipedia/commons/7/77/Blausen_0017_AlzheimersDisease.png.

It is unclear whether cortical atrophy (Fig. 2.5) always occurs in AD because it usually occurs in a different part of the brain (posterior brain cortex). Posterior cortical atrophy is often associated with Lewy body dementia or with Creutzfeld–Jakob disease.

Cell Membrane

As seen in Fig. 1.19, the cells in the body display many different shapes. Therefore, in this chapter, we will deal with an ideal model of a typical cell. An example is shown in cross section in Fig. 2.6. The higher eukaryotic cell that contains a distinct membrane-bound nucleus, shown here, contrasts with a prokaryotic cell, a bacterium or a cyanobacterium, that do not contain membrane-bound organelles and do not have their DNAs in the form of chromosomes. It also contrasts with the eukaryotic yeast cell that contains a rigid cell wall outside the plasma membrane. The cell membrane or the plasma membrane is the outermost layer surrounding the cell (Fig. 2.6) consisting of a double layer of lipids with polar head groups facing the exterior and interior. The lipid bilayer membrane is penetrated with transmembrane proteins with extensions to the outside of the cell and inside to contact the cytoplasm (Fig. 2.7). From the outside layer inward, the polar head groups are ammonium (NH4+), hydrocarbon chain of the fatty acid, and a phosphate group (substituent of glycerol, for one) on the interior side.

Figure 2.6 Cross-sectional model of a typical eukaryotic cell. Reproduced from http://www.rkm.com.au/CELL/cellimages/animal-cell-label.jpg.

Figure 2.7 Drawing of a section of the plasma membrane showing typical constituents. Reproduced from http://www.molecularstation.com/molecular-biology-images/data/504/CellMembraneDrawing.jpg.

The nonpolar stretches of the glycerol connected fatty acids meet in the middle of the two layers forming the nonpolar region. Each portion of the membrane consisting of a polar group on either end connected to nonpolar stretches in the middle is referred to as a leaflet (Fig. 2.8).

Figure 2.8 Diagram of the structure of one membrane leaflet showing a polar group at the top (outside) with the nonpolar hydrocarbon structure extending to the center of the cell membrane bilayer. An opposing leaflet (mirror image approximating a similar structure) creates the double layer membrane as shown in Fig. 2.7. Reproduced from Fig. 1.6 of Litwack, G., 2008. Human Biochemistry and Disease, Academic Press/Elsevier, p. 8.

Cholesterol, located between the hydrocarbon components (fatty acid chains), is a critical ingredient of the membrane and is present in about a one-to-one ratio with the phospholipid (Fig. 2.7). A phospholipid consists of 1 molecule of glycerol substituted by 2 molecules of fatty acids, a phosphate group, and a polar molecule; examples are phosphatidylcholine, phosphatidylethanolamine, or phosphatidic acid. The polar group attracts water and faces the interior aqueous cytoplasm while the nonpolar (hydrophobic; repels water) fatty acid tail faces away from the aqueous cytoplasm (see Chapter 9: Lipids). Cholesterol provides some rigidity to the otherwise flexible semipermeable membrane. Cholesterol also enhances the nonpolar solubility of the membrane for entry of nonpolar substances that can dissolve in and permeate the membrane, essentially by free diffusion. There are various groups protruding from the outside surface of the membrane. Glycolipids, for