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	Volume 1

	Preface	XXI
	List of Contributors	XXIII

Part I	Overview of Amyloidosis and Amyloid ProteinsContents



1	Amyloidosis and Amyloid Proteins: Brief History and Definitions Per Westermark	3
1.1	Early History	3
1.1.1	Initial Studies	3
1.1.2	Different Chemical Forms of Amyloid: Early Studies	5
1.1.3	Amyloid Staining Methodology	6
1.2	Amyloid Proteins -- Modern History	7
1.2.1	The Amyloid Proteins	7
1.2.2	Specific Amyloid Fibril Proteins	9
1.2.2.1	Protein AA and its Precursor, Serum AA	9
1.2.2.2	Immunoglobulin-derived Amyloid (AL and AH)	10
1.2.2.3	Transthyretin	11
1.2.2.4	Other Biochemical Forms of Familial Amyloidosis	12
1.2.2.5	₂-Microglobulin (₂M)	12
1.2.2.6	Specific Amyloid Forms in the Central Nervous System	12
1.2.2.7	Polypeptide Hormone-derived (Endocrine) Amyloid	13
1.2.2.8	Islet Amyloid Polypeptide	13
1.3	Classification of Amyloid Diseases	14
1.3.1	Reimanns Classification	14
1.3.2	Kings Classification	15
1.3.3	Classification of Missmahl et al.	15
1.3.4	Modern Classification	15
1.3.4.1	The Present Classification of Amyloid Fibril Proteins	15
1.4	What is Amyloid?	17
	Acknowledgments	18
	References	18
2	Anatomic and Clinical Clues to In Vivo Mechanisms of Amyloidogenesis Vittorio Bellotti, Laura Obici, Robert Kisilevsky and Giampaolo Merlini	29
2.1	Introduction	29
2.2	AA Amyloidogenesis	30
2.3	₂-Microglobulin (₂M) and the Amyloid Deposition in Hemodialysis	33
2.3.1	The Post-translation Modifications of ₂M in Naturally Occurring Amyloid Fibrils	33
2.3.2	The Interaction of ₂M with Collagen and Other Matrix Components	34
2.3.3	The Molecular Target of ₂M Amyloid Fibrils	34
2.4	Other Amyloid Proteins Display Unique Tissue Specificity	36
2.5	Local Production of Amyloidogenic Protein can Dictate the Occurrence of Localized Amyloidosis	39
2.6	Conclusions	41
	Acknowledgments	42
	References	42



Part II	Protein Structure and the Beta Pleated Sheet Conformation



3	The -pleated Sheet Conformation and Protein Folding: A Brief History Jean D. Sipe	49
3.1	Introduction	49
3.2	The -pleated Sheet Structure of the Amyloid Fibril	50
3.3	Polypeptide Backbone Folding: Steric Considerations	52
3.4	Polypeptide Backbone Folding: The Environment	57
3.5	Conclusion	60
	References	60



Part III	Protein Folding, Unfolding and Refolding



4	Thermodynamics and Protein Folding Ilia V. Baskakov	65

4.1	Introduction	65
4.2	Thermodynamic versus Kinetic Control of Protein Folding	65
4.3	What Thermodynamic Forces are Responsible for the Exceptional Stability of Amyloid Aggregates?	68
4.4	Single Polypeptide Chain--Multiple -Sheet-rich Abnormal Isoforms	69
4.5	Does the Process of Prion Propagation Differ from Formation of Ordered Amyloid Aggregates?	71
4.6	Prion Propagation is an Autocatalytic Process	72
4.7	Conformational Diversity of Self-propagating Prion Aggregates	74
4.8	High Species Specificity of Prion Propagation	74
4.9	Conclusions	76
	References	77
5	Role of Post-translational Chemical Modifications in Amyloid Fibril Formation Melanie R. Nilsson	81
5.1	Introduction	81
5.2	Common Modifications that May Play a Significant Role In Vivo	84
5.2.1	Cleavage by Proteases or Non-enzymatic Hydrolysis	84
5.2.2	Deamidation, Isomerization, Racemization and Protein L-Isoaspartyl Methyltransferase (PIMT)	88
5.2.3	Oxidative Damage	92
5.2.4	AGEs	93
5.2.5	Phosphorylation	94
5.3	Proposed Mechanisms by which Chemical Modifications may Affect Amyloid Deposition	94
5.4	Conclusions and Future Directions	98
	Acknowledgments	98
	References	98
6	Lipid Modulators of Protein Misfolding and Aggregation Christopher A. MacRaild and Geoffrey J. Howlett	111
6.1	Introduction	111
6.2	Protein Folding and Aggregation at Lipid Surfaces	112
6.2.1	The A Peptide	113
6.2.2	ApoAI	115
6.2.3	-Synuclein	116
6.2.4	Lipid Surfaces in Other Amyloidogenic Systems	116
6.3	Lipid Oxidation and Amyloid Formation	117
6.4	Apolipoproteins and Amyloid	118
6.5	The Effect of Lipids on the Stability of Apolipoproteins	119
6.6	Summary	120
	Acknowledgments	121
	References	122
7	Extracellular Matrix Heparan Sulfate Proteoglycans Peter J. Neame and John T. Gallagher	131
7.1	Introduction	131
7.2	Protein Folding and Glycosaminoglycans	134
7.3	-Sheets	136
7.4	Proteoglycans	138
7.4.1	Basement Membrane-derived Heparan Sulfate Proteoglycans	140
7.4.1.1	Agrin	140
7.4.1.2	Perlecan (HSPG2)	140
7.4.1.3	Collagen XVIII	141
7.4.2	Cell Surface Heparan Sulfate Proteoglycans	141
7.4.2.1	Glypicans	142
7.4.2.2	Syndecans	142
7.4.2.3	-Glycan	143
7.5	Heparin, Heparan Sulfate and Other Glycosaminoglycans	143
7.5.1	Chondroitin sulfate	144
7.5.2	Dermatan Sulfate	145
7.5.3	Heparan Sulfate	146
7.6	Heparin--Heparan Sulfate Interactions with Protein	147
7.7	Amyloid Proteins and Peptides	150
7.7.1	Light Chain Amyloid (AL)	150
7.7.2	Serum Amyloid P (SAP)	151
7.7.3	Inflammation-associated AA	151
7.7.4	₂-Microglobulin (₂M)	152
7.7.5	Transthyretin (ATTR)	152
7.7.6	Islet Amyloid (AIAPP)	153
7.7.7	Alzheimers A	154
7.8	Heparan Sulfate and Amyloid	155
7.9	Conclusion	156
7.10	Future Directions	157
	Acknowledgments	158
	References	158
8	Serum Amyloid P Component David C. Kilpatrick	169
8.1	Introduction to Pentraxins	169
8.2	Structure of SAP	172
8.3	Lectin and Other Biological Activities of SAP	174
8.4	SAP: Its Physiological Role in Health	178
8.5	SAP: Its Role in Disease	180
	References	182
9	Serum amyloid P Component -- Structural Features and Amyloid Recognition S.P. Wood and A.R. Coker	189
9.1	Introduction	189
9.2	Amyloid Fibrils and their Formation	190
9.3	The Structure of SAP	192
9.4	The Calcium-binding Site	196
9.5	Comparative studies of CRP	198
9.6	SAP Structure in the Absence of Calcium	198
9.7	Binding of Small Molecule Ligands to SAP	199
9.8	The Role of Glycosaminoglycans (GAGs)	203
9.9	SAP, Protein Folding and Amyloid Fibril Formation	204
9.10	Perspective	205
	References	206
10	Apolipoprotein E: Structural and Functional Interactions with Amyloid W. Blaine Stine Jr. and Mary Jo LaDu	211
10.1	Introduction	211
10.2	ApoE Background	211
10.2.1	Function in Plasma Lipid Metabolism	211
10.2.2	ApoE Structure	212
10.3	ApoE and A	215
10.3.1	Summary	215
10.3.2	ApoE and Neurodegenerative Diseases	216
10.3.3	A: Oligomers and Amyloid	217
10.3.4	ApoE and A Peptide	218
10.3.5	ApoE:A Binding Domains	221
10.3.6	ApoE and Amyloidosis	222
10.3.7	ApoE and Amyloid Deposition	223
10.3.8	ApoE Receptors in the CNS	224
10.3.9	ApoE and A-induced Neurotoxicity	224
10.3.10	Conclusion	225
10.4	Other A Binding Proteins	226
10.4.1	ApoJ	226
10.4.2	₂-macroglobulin (₂M) and ₁-antichymotrypsin (ACT)	227
	Acknowledgments	228
	References	228

Part IV	Pathway to Amyloid Fibril Formation

11	Pathways to Amyloid Fibril Formation: Partially Folded Intermediates in the Fibrillation of Natively Unfolded Proteins Vladimir N. Uversky and Anthony L. Fink	247
11.1	Introduction	247
11.2	Molecular Mechanisms of Amyloid Fibril Formation by a Natively Unfolded Protein: -Synuclein	250
11.2.1	-Synuclein in Parkinsons Disease and other Neurodegenerative Disorders	250
11.2.2	Key Structural Properties of -Synuclein: A Natively Unfolded Protein	251
11.2.3	Major Structural Characteristics of Partially Folded -Synuclein	252
11.2.4	Fibril Formation by -Synuclein and the Partially Folded Amyloidogenic Conformation	254
11.3	Fibrillogenesis of Natively Unfolded Proteins Requires Partial Folding	259
11.3.1	Fibril Formation by Proteins Involved in Conformational Disorders	259
11.3.2	Amyloid protein (Ab)	259
11.3.3	Tau protein	260
11.3.4	Islet Amyloid Polypeptide (IAPP) or Amylin	260
11.3.5	Prion Protein	261
11.3.6	Polyglutamine Repeat Diseases	262
11.4	Fibrillation of Proteins Unrelated to Conformational Disease	262
11.4.1	Yeast Prions	262
11.4.2	Prothymosin	263
11.4.3	Apolipoprotein CII (ApoCII)	263
11.4.4	Histones	264
11.5	Conclusions	264
	Acknowledgments	264
	References	265
12	Structural Intermediates of Globular Proteins as Precursors to Amyloid Formation Daniel F. Moriarty and Wilfredo Coln	275
12.1	Introduction	275
12.2	Protein Folding	276
12.3	Folding Intermediates as Precursors to Protein Aggregation	277
12.4	Structural Intermediates in Amyloid Formation	278
12.4.1	TTR	280
12.4.2	₂-Microglobulin (₂M)	280
12.4.3	Lysozyme	281
12.4.4	Cystatin C	281
12.4.5	Serum Amyloid A (SAA)	282
12.5	Factors that Favor the Formation of Amyloidogenic Intermediates	282
12.5.1	Thermodynamic versus Kinetic Stability Effects	282
12.5.2	The Effect of Aging on Amyloid Formation	283
12.5.3	From -Helix to -Sheet: “Jekyll and Hyde Sequences”	284
12.6	Mechanism of Amyloid Formation	285
12.6.1	Nucleation-dependent Amyloid Fibril Formation	285
12.6.2	Partial versus Global Unfolding	287
12.7	An “Eye” for an “I”: Inhibiting the Formation of Intermediates	289
12.7.1	Native State Stabilization via Binding of Small Molecules	289
12.7.2	Native State Stabilization via Binding of Protein Molecules	290
12.7.3	Therapeutic Potential	291
12.8	Conclusion	291
	References	292
13	Computational Approaches and Tools for Establishing Structural Models for Short Amyloid-forming Peptides Nurit Haspel, David Zanuy, Hui-Hsu (Gavin) Tsai, Buyong Ma, Haim Wolfson and Ruth Nussinov	301

13.1	Introduction	301
13.2	Computational Tools in the Service of Amyloid Structure Prediction	302
13.3	Constructing Amyloid Models	303
13.4	The Calcitonin Pentapeptide System: Bulk Organization and Interactions	305
13.5	Calcitonin Mutation Study: Simulation and Prediction of Specific Changes in Amino Acids	311
13.6	DFNKF Amyloid Seed and its Stability and Dynamics	312

13.7	Conclusions	312
	Acknowledgments	313
	References	313

Part V	Pathophysiology of Amyloid Fibril Formation

14	Oligomers and Cellular Toxicity Bruce Kagan	319
14.1	Introduction	319
14.2	Aggregation	321
14.3	Cellular Mechanisms of Oligomeric Toxicity	324
14.4	Loss of Function Hypothesis	325
14.5	Receptors for Advanced End-products of Glycation (RAGE) Receptors	325
14.6	Oxidative Stress	326
14.7	The Channel Hypothesis	326
14.8	A	326
14.9	PrP106-126	329
14.10	IAPP	331
14.11	ANP	332
14.12	SAA	332
14.13	AS	333
14.14	₂M	334
14.15	AL Amyloidosis	335
14.16	PG	335
14.17	HypF	336
14.18	Calcitonin (CT)	336
14.19	Lysozyme	337
	References	337
15	The Future of Molecular Diagnostics and Targeted Therapeutics in the Amyloidoses David C. Seldin	343
15.1	Introduction	343
15.2	Early Diagnosis of Amyloid Diseases	344
15.3	Accurate Classification of Amyloid Diseases	348
15.4	Non-invasive Staging of Amyloid Diseases	349
15.5	Targeted Therapeutics of Amyloid Diseases	350
15.6	Amyloid Disease Prevention	351
15.7	Conclusions	353
	References	353
16	Brain Dysfunction Associated with Amyloid Fibrils and Other Aggregated Proteins Giorgio Giaccone, Mario Salmona, Fabrizio Tagliavini and Gianluigi Forloni	355
16.1	Introduction	355
16.2	Neuropathology	357
16.2.1	Alzheimers Disease	357
16.2.2	Tauopathies	361
16.2.3	Prion Diseases	365
16.2.4	Synucleinopathies	367
16.3	The Neurotoxic Proteins	370
16.3.1	Alzheimers Disease	370
16.3.2	Prion Diseases	371
16.3.3	Synucleinopathies	373
16.4	Conclusions	375
	References	375


	Volume 2

Part VI	Amyloid Proteins

	Brain	385
17	The Amyloid Protein Noel D. Lazo, Samir K. Maji, Erica A. Fradinger, Gal Bitan and David B. Teplow	385

17.1	Introduction	385
17.2	Ab, AD and Amyloid	386
17.3	Pathogenetic Process -- Biology	388
17.3.1	A Metabolism and AD	388
17.3.2	Mechanisms of A-induced Neuronal Injury	394
17.4	Normal Physiologic Function of APP and A	398
17.4.1	APP Structure	398
17.4.2	APP and A Function	398
17.5	Genetic Evidence for a Role of A in AD	401
17.5.1	Mutations in APP	402
17.5.1.1	Mutations Inside the A Region of APP	402
17.5.1.2	Mutations Outside the A Region of APP	406
17.5.2	Mutations in PSEN1 and PSEN2	407
17.5.3	APOE is an AD risk factor	408
17.5.4	Other Genetic Factors	409
17.6	Pathogenetic Process -- Biophysics	409
17.6.1	A Folding and Assembly -- From Fibrils Back to Monomers	410
17.6.1.1	Fibrils	410
17.6.1.2	Protofibrils	415
17.6.1.3	-Helical Intermediate	417
17.6.1.4	Micelles	418
17.6.1.5	ADDLs	419
17.6.1.6	Paranuclei	420
17.6.2	A Monomer Folding	421
17.6.3	Other A Assemblies	424
17.6.3.1	Channels	424
17.6.3.2	amy Balls	425
17.6.3.3	Amylospheroids (ASPDs)	425
17.6.4	Modulators of A Folding and Assembly	426
17.6.4.1	Proteins	426
17.6.4.2	Lipids	431
17.6.4.3	Metal Ions	433
17.7	Identification of Therapeutic Targets	433
17.7.1	Fibrils	434
17.7.2	Protofibrils	435
17.7.3	-Helix-rich Intermediate	435
17.7.4	Oligomers	436
17.7.5	Targeting A Conformation	436
17.7.5.1	Stabilization of Native Conformation	436
17.7.5.2	(De)stabilization of Specific Conformers	436
17.7.5.3	A Monomer Subregions and Residues	437
17.7.5.4	Central Hydrophobic Cluster (CHC)	439
17.8	Current Therapies for AD	443
17.8.1	Approved Drugs	443
17.8.1.1	AChE Inhibitors (AChEIs)	443
17.8.1.2	Memantine	444
17.8.1.3	Antioxidants	444
17.8.2	Clinical Studies	444
17.8.2.1	Immunotherapy	444
17.8.2.2	Statins	445
17.8.2.3	Chelation Therapy	445
17.8.2.4	Hormone Replacement Therapy	446
17.8.2.5	Anti-inflammatory Drugs	446
17.8.2.6	Natural Products	446
17.8.3	Pre-clinical Studies	447
17.8.4	ccelerating Progress Toward a Cure	447
17.9	Concluding Remarks	448
	References	448
18	Prion Protein Philippe Derreumaux	493
18.1	Introduction	493
18.2	Conformations of PrP^C and PrP^Sc	496
18.3	Stability and Unfolding/Folding of PrP^C in vitro	499
18.4	Mechanisms of Prion Replication In Vivo	501
18.5	Perspectives	505
	References	506
19	Familial British and Danish Dementias Jorge Ghiso, Agueda Rostagno, Yasushi Tomidokoro, Tammaryn Lashley, Janice L. Holton, Gordon Plant, Tamas Revesz and Blas Frangione	515
19.1	Introduction	515
19.2	FBD and FDD	515
19.2.1	Clinical Presentation	515
19.2.2	Neuropathology	516
19.3	A Novel Gene BRI2	517
19.4	BRI2 Mutations Generate Two New Amyloid Subunits, ABri and ADan	520
19.5	Biochemical Properties of Amyloid Subunits ABri and ADan	521
19.6	Soluble Forms of ABri and ADan in Biological Fluids	522
19.7	Unique Features of FBD or FDD	522
19.7.1	FBD is a Systemic Disorder	522
19.7.2	FDD is Not a Single Amyloid Disease	523
19.8	Potential Implications of FBD and FDD for Alzheimer's Disease	523
	Acknowledgments	523
	References	524
	Systemic	527
20	Immunoglobulin Fred J. Stevens	527
20.1	Introduction	527
20.2	Amyloidosis (AL)	529
20.3	Physicochemistry of Antibody Light Chains	532
20.3.1	Self-association of Variable Domains	532
20.3.2	Variable Domain Stability	535
20.4	Database of Dyscrasia-related Variable Domain Sequences	544
20.5	Amyloidosis (AH)	547
20.6	Immunoproteomics	548
20.7	Concluding Remarks	553
	Acknowledgments	553
	References	554
21	Transthyretin Ana Margarida Damas and Maria Joa\~o Saraiva	571
21.1	Introduction	571
21.2	Gene Structure and Regulation	572
21.3	Function	573
21.4	Three-dimensional Structure of TTR	574
21.5	TTR Amyloidosis (ATTR)	576
21.6	TTR Amyloid Inhibitors	578
21.7	Ligand Binding	580
21.8	Post-translational Modifications	581
21.9	Evolution	582
	References	583
22	High-Density Lipoprotein Amyloid Proteins Barbara Kluve-Beckerman	589
22.1	Introduction	589
22.2	SAA [Secondary, Reactive, Amyloid A (AA) Amyloidosis]	589
22.2.1	Background	589
22.2.2	Gene and Protein (Primary) Structure	590
22.2.3	Polymorphisms and Amyloidogenicity	592
22.2.4	Protein Structure (Three-dimensional)	595
22.2.5	Induction of Protein Synthesis	596
22.2.6	Association with HDL	597
22.2.7	Catabolism, Macrophages and Amyloidogenesis	597
22.3	ApoAI Amyloidosis	599
22.3.1	Background	599
22.3.2	Gene and Protein Structure	600
22.3.3	Association with HDL	602
22.3.4	Amyloidogenic Variants of ApoAI	602
22.3.4.1	Gly26Arg	603
22.3.4.2	Trp50Arg	604
22.3.4.3	Leu60Arg	604
22.3.4.4	Leu64Pro	604
22.3.4.5	Del 60-71, Ins Val--Thr	605
22.3.4.6	Del 70-72	605
22.3.4.7	Leu75Pro	605
22.3.4.8	Leu90Pro	606
22.3.4.9	Arg173Pro	606
22.3.4.10	Leu174Ser	607
22.3.4.11	Ala175Pro	607
22.3.4.12	Leu178His	607
22.4	ApoAII Amyloidosis	608
22.4.1	Background	608
22.4.2	Gene and Protein Structure	609
22.4.3	Association with HDL and Potential Function	610
22.4.4	Amyloidogenic Variants of Human ApoAII	612
22.4.4.1	Stop78Gly	612
22.4.4.2	Stop78Ser	613
22.4.4.3	Stop78Arg	613
22.4.5	Mouse ApoAII Amyloidosis	613
22.5	Conclusion	614
	References	615
23	Gelsolin Hadar Benyamini, Kannan Gunasekaran, Haim Wolfson and Ruth Nussinov	625
23.1	Physiology, Pathology and Genetics	625
23.1.1	Gelsolin Amyloidosis	625
23.1.2	Normal and Mutant Protein Function	625
23.1.3	Gelsolin Amyloid Genetics	626
23.2	Mechanism of Amyloid Formation by Gelsolin	627
23.2.1	Cell Biology	627
23.2.2	Domain Stability and Amyloid Formation	628
23.3	Conclusions	631
	Acknowledgments	631
	References	632
24	Lysozyme Mireille Dumoulin, Vittorio Bellotti and Christopher M. Dobson	635
24.1	Introduction	635
24.2	Lysozyme in Healthy Subjects	636
24.3	Clinical Manifestations of Lysozyme Amyloidosis	636
24.4	Characteristics of Ex Vivo and In Vitro Amyloid Fibrils	638
24.5	In Vitro Studies of the Properties of the Variant Lysozymes	640
24.5.1	Effects of Mutations on the Native Structure of Lysozyme	640
24.5.2	Effects of the Mutations on the Folding of Lysozyme	642
24.5.2.1	Equilibrium Unfolding	642
24.5.2.2	Kinetics of Unfolding and Refolding	643
24.5.3	Effect of the Mutations on the Conformational Dynamics of Lysozyme	646
24.6	Mechanism of Fibril Formation	648
24.7	Conclusion and Future Perspectives	653
	Acknowledgments	654
	References	654
25	Fibrinogen Gilles Grateau and Marc Delpech	657
25.1	Introduction	657
25.2	Clinical Manifestations	657
25.2.1	Amyloid Nephropathy is the Main Clinical Feature of AFib Amyloidosis	658
25.2.2	Other Manifestations of AFib Amyloid	658
25.2.3	Diagnosis of AFib Amyloidosis	658
25.2.4	Treatment	659
25.3	The Fibrinogen Molecule	660
25.4	The Various AFib Mutations and Related Peptides	661
25.4.1	R554L Mutation	661
25.4.2	E526V Mutation	662
25.4.3	E540V Mutation	662
25.4.4	4904delG Mutation	662
25.4.5	4897delT Mutation	663
25.4.6	517-522 Delin Complex Mutation	663
25.5	Mechanisms of AFib Amyloidosis	663
	Acknowledgments	664
	References	665
26	₂-Microglobulin Thomas R. Jahn and Sheena E. Radford	667
26.1	Introduction: Dialysis-related Amyloidosis: A Deposition Disorder of ₂-Microglobulin (₂M)	667
26.2	Current Knowledge of the Mechanism of Development of DRA In Vivo	669
26.2.1	₂M: Normal Cellular Role	669
26.2.2	Clinical Manifestation and Diagnosis of DRA	670
26.2.3	Composition of Dialysis-Related Amyloid (DRA)	672
26.2.3.1	₂M in Amyloid Deposits and Associated Biological Factors	672
26.2.3.2	GAGs, Proteoglycans (PGs) and Collagen	673
26.2.3.3	AGE Modification	674
26.2.3.4	Macrophages	674
26.2.3.5	Inflammation	675
25.2.3.6	Influence of Dialysis Procedure	675
26.3	Structure and Morphology of ₂M Amyloid Fibrils	676
26.3.1	Amyloid Formation from ₂M In Vitro	676
26.3.2	Initial Progress towards the Structure of ₂M Amyloid Fibrils in Atomic Detail	678
26.3.3	Mechanisms of Fibril Formation	680
26.4	Structural Characteristics of Monomeric Fibril Precursor States	681
26.4.1	Predicting Regions Key to the Formation of Amyloid by ₂M	681
26.4.2	Partially Unfolded Species as Precursors of Amyloidosis	684
26.4.3	Factors Facilitating Fibril Formation	685
26.4.3.1	Proteolysis	685
26.4.3.2	Mutational Analysis	685
26.4.3.3	Rare Unfolding Events	686
26.4.3.4	Copper	686
26.4.3.5	A Consensus Model?	687
26.5	Summary and Future Implications	688
	Acknowledgments	689
	References	689
27	Cystatin C Mariusz Jaskolski and Anders Grubb	697
27.1	Introduction	697
27.2	Biochemical and Physiological Characteristics	697
27.3	HCCAA	699
27.4	Cystatin C Oligomers In Vivo and In Vitro	700
27.5	The Phenomenon of Three-dimensional Domain Swapping	700
27.6	The Cystatin Fold	703
27.7	Three-dimensional Domain Swapping in Full-length Cystatin C	703
27.8	Three-dimensional Domain Swapping in N-truncated Cystatin C	705
27.9	Structural Implications for L68Q Cystatin C	708
27.10	Higher Oligomers Observed by Crystallography and Other Methods	710
27.11	In Vivo Amyloid Deposits Containing Cystatin C	712
27.12	Formation of Cystatin C Amyloid Fibrils In Vitro	713
27.13	Inhibition of Dimerization and Fibril Formation by Protein Engineering	714
27.14	Inhibition of Dimerization by Monoclonal Antibodies and Carboxymethylpapain	716
27.15	Outlook	717
	Acknowledgments	718
	References	718
	Hormone	723
28	Endocrine Amyloid Gunilla T. Westermark	723
28.1	Nomenclature for Endocrine Amyloid	723
28.2	When and Why do Proteins form Amyloid?	723
28.3	Amyloid in Cardiac Atria	725
28.3.1	Heart as an Endocrine Organ	725
28.3.2	Atrial Amyloid	726
28.3.3	Isolation and Characterization of Atrial Amyloid	727
28.3.4	Are there Clinical Implications for IAA?	728
28.4	Endocrine Amyloid in the Thyroid	729
28.4.1	Amyloid in Medullary Carcinomas	729
28.4.2	Can Amyloid be of Benefit?	730
28.5	Amyloid Deposits in the Pituitary	730
28.5.1	Prolactin as an Amyloid Fibril Protein	731
28.5.2	Prolactin Deposited as Amyloid in the Aged Pituitary	732
28.6	Endocrine Amyloid in the Islets of Langerhans	732
28.6.1	IAPP Amyloid and its Putative Role for the Development of Type 2 Diabetes	733
28.6.2	IAPP	734
28.6.3	Expression of IAPP	735
28.6.4	Biological Activity of IAPP	736
28.6.4.1	Autocrine or Paracrine Effect on the Islet Cells	736
28.6.4.2	Calcium Metabolism	737
28.6.4.3	IAPP and Satiety	737
28.6.5	Amyloidogenic Properties of the IAPP Molecule	738
28.6.6	Pathogenesis of Islet Amyloid and Cellular Effects of Aggregated IAPP	739
28.6.7	Transgenic Animals	740
28.7	Insulin as an Amyloid-forming Protein	741
28.8	Can Other Islet Hormones Aggregate and Form Amyloid?	742
28.9	Other Amyloids with Possible Endocrine Origin	742
28.9.1	Parathyroid Gland	742
	Acknowledgments	743
	References	743
	Glossary of Terms	755
	Subject Index	759

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