Targeting protein aggregation for the treatment of degenerative diseases

Nature Reviews Drug Discovery

Volumn 14, Issue 11, 2015, Pages 759-780

  Eisele, Yvonne S ^a   Monteiro, Cecilia ^a   Fearns, Colleen ^a   Encalada, Sandra E ^a   Wiseman, R Luke ^a   Powers, Evan T ^a   Kelly, Jeffery W ^a  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID; AMYLOID A PROTEIN; BETA SECRETASE; CHAPERONE; CHAPERONIN; DIFLUNISAL; DNA BINDING PROTEIN; GAMMA SECRETASE; HEAT SHOCK PROTEIN 90; HEAT SHOCK TRANSCRIPTION FACTOR 1; HUNTINGTIN; IMMUNOGLOBULIN LIGHT CHAIN; NONSTEROID ANTIINFLAMMATORY AGENT; PREALBUMIN; PROTEASOME; RNA; TAFAMIDIS; TAU PROTEIN; TRANSCRIPTION FACTOR FKHR; BIOLOGICAL FACTOR;

ALZHEIMER DISEASE; AMYLOIDOSIS; AMYOTROPHIC LATERAL SCLEROSIS; CONFORMATIONAL TRANSITION; DEGENERATIVE DISEASE; FRONTOTEMPORAL DEMENTIA; HEREDITY; HUMAN; HYDROPHOBICITY; IN VIVO STUDY; LYSOSOME; NITROSYLATION; PARKINSON DISEASE; POINT MUTATION; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN FOLDING; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; PROTEIN TARGETING; REVIEW; RISK FACTOR; RNA SPLICING; STRUCTURE ACTIVITY RELATION; TISSUE DEGENERATION; ANIMAL; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG EFFECTS; METABOLISM; NEURODEGENERATIVE DISEASES; PATHOLOGY; PROTEIN AGGREGATION, PATHOLOGICAL; PROTEIN TRANSPORT; TREATMENT OUTCOME;

ANIMALS; BIOLOGICAL FACTORS; HUMANS; NEURODEGENERATIVE DISEASES; PREALBUMIN; PROTEIN AGGREGATION, PATHOLOGICAL; PROTEIN FOLDING; PROTEIN TRANSPORT; STRUCTURE-ACTIVITY RELATIONSHIP; TREATMENT OUTCOME;

EID: 84946475663     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd4593     Document Type: Review

References (307)

1. Andrade, C A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 75, 408-427 (1952
2. Glenner, G. G., Terry, W., Harada, M., Isersky, C., & Page, D. Amyloid fibril proteins: proof of homology with immunoglobulin light chains by sequence analyses. Science 172, 1150-1151 (1971
3. Linke, R. P., et al. Characteristics of a serum substance (SAA) antigenically related to amyloid fibril protein AA. Z. Immunitätsforsch. Exp. Klin. Immunol. 150, 219-219 (1975
4. Glenner, G. G., & Wong, C. W. Alzheimer's disease, and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem. Biophys. Res. Commun. 122, 1131-1135 (1984
5. Sipe, J. D., et al. Nomenclature 2014: amyloid fibril proteins, and clinical classification of the amyloidosis. Amyloid 21, 221-224 (2014
6. Eisenberg, D., & Jucker, M. The amyloid state of proteins in human diseases. Cell 148, 1188-1203 (2012)
7. Bonar, L., Cohen, A. S., & Skinner, M. M. Characterization of amyloid fibril as a cross-β protein. Proc. Soc. Exp. Biol. Med. 131, 1373-1375 (1969
8. Holmes, B. B., et al. Heparan sulfate proteoglycans mediate internalization, and propagation of specific proteopathic seeds. Proc. Natl Acad. Sci. USA 110, E3138-E3147 (2013
9. Udan-Johns, M., et al. Prion-like nuclear aggregation of TDP 43 during heat shock is regulated by HSP40/70 chaperones. Hum. Mol. Genet. 23, 157-170 (2014
10. Yanamandra, K., et al. Anti-Tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology, and improve cognition in vivo. Neuron 80, 402-414 (2013
11. Oddo, S., et al. Triple-Transgenic model of Alzheimer's disease with plaques, and tangles: intracellular Aβ, and synaptic dysfunction. Neuron 39, 409-421 (2003
12. Knauer, M. F., Soreghan, B., Burdick, D., Kosmoski, J., & Glabe, C. G. Intracellular accumulation, and resistance to degradation of the Alzheimer amyloid A4/β protein. Proc. Natl Acad. Sci. USA 89, 7437-7441 (1992
13. Ferretti, M. T., Bruno, M. A., Ducatenzeiler, A., Klein, W. L., & Cuello, A. C. Intracellular Aβ-oligomers, and early inflammation in a model of Alzheimer's disease. Neurobiol. Aging 33, 1329-1342 (2012
14. Hong, M. G., Alexeyenko, A., Lambert, J. C., Amouyel, P., & Prince, J. A. Genome-wide pathway analysis implicates intracellular transmembrane protein transport in Alzheimer disease. J. Hum. Gen. 55, 707-709 (2010
15. Sahlin, C., et al. The Arctic Alzheimer mutation favors intracellular amyloid-β production by making amyloid precursor protein less available to α-secretase. J. Neurochem. 101, 854-862 (2007
16. Page, L. J., et al. Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins. Proc. Natl Acad. Sci. USA 106, 11125-11130 (2009
17. Eisele, Y. S., et al. Peripherally applied Aβ-containing inoculates induce cerebral β-Amyloidosis. Science 330, 980-982 (2010
18. Kfoury, N., Holmes, B. B., Jiang, H., Holtzman, D. M., & Diamond, M. I. Trans-cellular propagation of tau aggregation by fibrillar species. J. Biol. Chem. 287, 19440-19451 (2012
19. Frost, B., Jacks, R. L., & Diamond, M. I. Propagation of tau misfolding from the outside to the inside of a cell. J. Biol. Chem. 284, 12845-12852 (2009
20. Luk, K. C., et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949-953 (2012
21. Tanzi, R. E., & Bertram, L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120, 545-555 (2005
22. Coelho, T., et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 79, 785-792 (2012
23. Coelho, T., et al. Long-Term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J. Neurol. 260, 2802-2814 (2013
24. Berk, J. L., et al. Repurposing diflunisal for familial amyloid polyneuropathy a randomized clinical trial. JAMA 310, 2658-2667 (2013
25. Hammarstrom, P., Schneider, F., & Kelly, J. W. Trans-suppression of misfolding in an amyloid disease. Science 293, 2459-2462 (2001
26. Hammarstrom, P., Wiseman, R. L., Powers, E. T., & Kelly, J. W. Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299, 713-716 (2003
27. Kastritis, E., et al. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J. Clin. Oncol. 28, 1031-1037 (2010
28. Merlini, G., Comenzo, R. L., Seldin, D. C., Wechalekar, A., & Gertz, M. A. Immunoglobulin light chain amyloidosis. Expert Rev. Hematol. 7, 143-156 (2014
29. Caughey, B., & Lansbury, P. T. Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu. Rev. Neurosci. 26, 267-298 (2003
30. Lachmann, H. J., et al. Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy. Br. J. Haematol. 122, 78-84 (2003
31. Bulawa, C. E., et al. Tafamidis, a potent, and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc. Natl Acad. Sci. USA 109, 9629-9634, (2012
32. Bacskai, B. J., et al. Imaging of amyloid-β deposits in brains of living mice permits direct observation of clearance of plaques with immunotherapy. Nat. Med. 7, 369-372 (2001
33. Colon, W., & Kelly, J. W. Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 31, 8654-8660 (1992
34. Hurle, M. R., Helms, L. R., Li, L., Chan, W., & Wetzel, R A role for destabilizing amino acid replacements in light-chain amyloidosis. Proc. Natl Acad. Sci. USA 91, 5446-5450 (1994
35. Pan, K. M., et al. Conversion of α-helices into β-sheets features in the formation of the Scrapie prion proteins. Proc. Natl Acad. Sci. USA 90, 10962-10966 (1993
36. Booth, D. R., et al. Instability, unfolding, and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 385, 787-793 (1997
37. Dobson, C. M. Protein folding, and misfolding. Nature 426, 884-890 (2003
38. Dyson, H. J., & Wright, P. E. Intrinsically unstructured proteins, and their functions. Nat. Rev. Mol. Cell Biol. 6, 197-208 (2005
39. Lee, J. P., et al. 1H NMR of Aβ amyloid peptide congeners in water solution. Conformational changes correlate with plaque competence. Biochemistry 34, 5191-5200 (1995
40. De Strooper, B., et al A presenilin 1 dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518-522 (1999
41. Haass, C., et al. The Swedish mutation causes early-onset Alzheimer's disease by β-secretase cleavage within the secretory pathway. Nat. Med. 1, 1291-1296 (1995
42. Ross, C. A. Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease, and related disorders. Neuron 35, 819-822 (2002
43. Sathasivam, K., et al. Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc. Natl Acad. Sci. USA 110, 2366-2370 (2013
44. Graham, R. K., et al. Cleavage at the caspase 6 site is required for neuronal dysfunction, and degeneration due to mutant huntingtin. Cell 125, 1179-1191 (2006
45. La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E., & Fischbeck, K. H. Androgen receptor gene mutations in X linked spinal, and bulbar muscular atrophy. Nature 352, 77-79 (1991
46. Chen, S., Ferrone, F. A., & Wetzel, R. Huntington's disease age of onset linked to polyglutamine aggregation nucleation. Proc. Natl Acad. Sci. USA 99, 11884-11889 (2002
47. Kosik, K. S., Joachim, C. L., & Selkoe, D. J. MicrotubuIe-Associated protein tau (?) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc. Natl Acad. Sci. USA 83, 4044-4048 (1986
48. Polymeropoulos, M. H., et al. Mutation in the á-synuclein gene identified in families with Parkinson's disease. Science 276, 2045-2047 (1997
49. Wolfe, M. S. Tau mutations in neurodegenerative diseases. J. Biol. Chem. 284, 6021-6025 (2009
50. Drewes, G., et al. Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J. 11, 2131-2138 (1992
51. Burre, J., Sharma, M., & Sudhof, T. C. α-synuclein assembles into higher-order multimers upon membrane binding to promote SNARE complex formation. Proc. Natl Acad. Sci. USA 111, E4274-E4283 (2014
52. Bartels, T., Choi, J. G., & Selkoe, D. J. α-synuclein occurs physiologically as a helically folded tetramer that resists aggregation. Nature 477, 107-110 (2011
53. Wang, L., et al. α-synuclein multimers cluster synaptic vesicles, and attenuate recycling. Curr. Biol. 24, 2319-2326 (2014
54. Neumann, M., et al. Ubiquitinated TDP 43 in frontotemporal lobar degeneration, and amyotrophic lateral sclerosis. Science 314, 130-133 (2006
55. Shelkovnikova, T. A., Robinson, H. K., Southcombe, J. A., Ninkina, N., & Buchman, V. L. Multistep process of FUS aggregation in the cell cytoplasm involves RNA-dependent, and RNA-independent mechanisms. Hum. Mol. Genet. 23, 5211-5226 (2014
56. DeJesus-Hernandez, M., et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p linked FTD, and ALS. Neuron 72, 245-256 (2011
57. Olzscha, H., et al. Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144, 67-78 (2011
58. Laganowsky, A., et al. Atomic view of a toxic amyloid small oligomer. Science 335, 1228-1231 (2012
59. Lashuel, H. A., Hartley, D., Petre, B. M., Walz, T., & Lansbury, P. T. Jr. Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418, 291 (2002
60. Ferrone, F. Analysis of protein aggregation kinetics. Methods Enzymol. 309, 256-274 (1999
61. Powers, E. T., & Powers, D. L. The kinetics of nucleated polymerizations at high concentrations: amyloid fibril formation near, and above the supercritical concentration. Biophys. J. 91, 122-132 (2006
62. Jarrett, J. T., & Lansbury, P. T. Jr. Seeding one-dimensional crystallization of amyloid: a pathogenic mechanism in Alzheimer's disease, and scrapie? Cell 73, 1055-1058 (1993
63. Serio, T. R., et al. Nucleated conformational conversion, and the replication of conformational information by a prion determinant. Science 289, 1317-1321 (2000
64. Hofrichter, J., Ross, P. D., & Eaton, W. A. Kinetics, and mechanism of deoxyhemogloblin S gelation: a new approach to understanding sickle cell disease. Proc. Natl Acad. Sci. USA 71, 4864-4868 (1974
65. Ferrone, F. A., Hofrichter, J., & Eaton, W. A. Kinetics of sickle hemoglobin poloymerization. II A double nucleation mechansim. J. Mol. Biol. 183, 611-631 (1985
66. Lundmark, K., et al. Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc. Natl Acad. Sci. USA 99, 6979-6984 (2002
67. Aguzzi, A., & Rajendran, L. The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron 64, 783-790 (2009
68. Hurshman, A. R., White, J. T., Powers, E. T., & Kelly, J. W. Transthyretin aggregation under partially denaturing conditions is a downhill polymerization. Biochemistry 43, 7365-7381 (2004
69. Terry, R. D., et al. Physical basis of cognitive alterations in Alzheimers disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30, 572-580 (1991
70. Cheng, I. H., et al. Accelerating amyloid-β fibrillization reduces oligomer levels, and functional deficits in Alzheimer disease mouse models. J. Biol. Chem. 282, 23818-23828 (2007
71. Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R., & Finkbeiner, S. Inclusion body formation reduces levels of mutant huntingtin, and the risk of neuronal death. Nature 431, 805-810 (2004
72. Palladini, G., et al Circulating amyloidogenic free light chains, and serum N terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL. Blood 107, 3854-3858 (2006
73. Simsek, I., et al. No regression of renal amyloid mass despite remission of nephrotic syndrome in a patient with TRAPS following etanercept therapy. J. Nephrol. 23, 119-123 (2010
74. Winner, B., et al. In vivo demonstration that α-synuclein oligomers are toxic. Proc. Natl Acad. Sci. USA 108, 4194-4199 (2011
75. Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W., & Dillin, A. Opposing activities protect against age-onset proteotoxicity. Science 313, 1604-1610 (2006
76. Sousa, M. M., Cardoso, I., Fernandes, R., Guimaraes, A., & Saraiva, M. J. Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of nonfibrillar aggregates. Am. J. Pathol. 159, 1993-2000 (2001
77. Bieschke, J., et al. Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils. Nat. Chem. Biol. 8, 93-101 (2012
78. Lee, J., Culyba, E. K., Powers, E. T., & Kelly, J. W. Amyloid-β forms fibrils by nucleated conformational conversion of oligomers. Nat. Chem. Biol. 7, 602-609 (2011
79. Garai, K., & Frieden, C. Quantitative analysis of the time course of Aβ oligomerization, and subsequent growth steps using tetramethylrhodamine-labeled Aβ. Proc. Natl Acad. Sci. USA 110, 3321-3326 (2013
80. Lashuel, H. A., Wurth, C., Woo, L., & Kelly, J. W. The most pathogenic transthyretin variant, L55P, forms amyloid fibrils under acidic conditions, and protofilaments under physiological conditions. Biochemistry 38, 13560-13573 (1999
81. Goate, A., et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704-706 (1991
82. Theuns, J., et al. Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. Am. J. Hum. Genet. 78, 936-946 (2006
83. Zigman, W. B., & Lott, I. T. Alzheimer's disease in Down syndrome: neurobiology, and risk. Ment. Retard. Dev. Disabil. Res. Rev. 13, 237-246 (2007
84. Chartier-Harlin, M. C., et al. á-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167-1169 (2004
85. Herlenius, G., Wilczek, H. E., Larsson, M., & Ericzon, B. G. Ten years of international experience with liver transplantation for familial amyloidotic polyneuropathy: results from the Familial Amyloidotic Polyneuropathy World Transplant Registry. Transplantation 77, 64-71 (2004
86. Holmgren, G., et al. Clinical improvement, and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 341, 1113-1116 (1993
87. Ihse, E., et al. Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis. J. Pathol. 216, 253-261 (2008
88. Wilczek, H. E., Larsson, M., Ericzon, B. G., & FAPWTR. Long-Term data from the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR). Amyloid 18, 193-195 (2011
89. Yamashita, T., et al. Long-Term survival after liver transplantation in patients with familial amyloid polyneuropathy. Neurology 78, 637-643 (2012
90. Antoni, G., et al. In vivo visualization of amyloid deposits in the heart with 11C PIB, and PET. J. Nuclear Med. 54, 213-220 (2013
91. Delahaye, N., et al. Impact of liver transplantation on cardiac autonomic denervation in familial amyloid polyneuropathy. Medicine 85, 229-238 (2006
92. Suhr, O. B. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' symptoms, and complications. Amyloid 10, 77-83 (2003
93. Rydh, A., et al. Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation. Eur. J. Nucl. Med. 25, 709-713 (1998
94. Stangou, A. J., et al. Hereditary fibrinogen A α-chain amyloidosis: phenotypic characterization of a systemic disease, and the role of liver transplantation. Blood 115, 2998-3007 (2010
95. Olofsson, B. O., Backman, C., Karp, K., & Suhr, O. B. Progression of cardiomyopathy after liver transplantation in patients with familial amyloidotic polyneuropathy, Portuguese type. Transplantation 73, 745-751 (2002
96. Munar-Ques, M., et al. Vitreous amyloidosis after liver transplantation in patients with familial amyloid polyneuropathy: ocular synthesis of mutant transthyretin. Amyloid 7, 266-269 (2000
97. Maia, L. F., et al. CNS involvement in V30M transthyretin amyloidosis: clinical, neuropathological, and biochemical findings. J. Neurol. Neurosurg. Psychiatry (2014
98. Gertz, M. A. Immunoglobulin light chain amyloidosis: 2011 update on diagnosis, risk-stratification, and management. Am. J. Hematol. 86, 181-186 (2011
99. Arendt, B. K., et al. Biologic, and genetic characterization of the novel amyloidogenic lamda light chain-secreting human cell lines, ALMC 1, and ALMC 2. Blood 112, 1931-1941 (2008
100. Monis, G. F., et al. Role of endocytic inhibitory drugs on internalization of amyloidogenic light chains by cardiac fibroblasts. Am. J. Pathol. 169, 1939-1952 (2006
101. Shi, J., et al. Amyloidogenic light chains induce cardiomyocyte contractile dysfunction, and apoptosis via a non-canonical p38α MAPK pathway. Proc. Natl Acad. Sci. USA 107, 4188-4193 (2010
102. Comenzo, R. L. Current, and emerging views, and treatments of systemic immunoglobulin light-chain (AL) amyloidosis. Contrib. Nephrol. 153, 195-210 (2007
103. Obici, L., & Merlini, G. Amyloidosis in autoinflammatory syndromes. Autoimmun. Rev. 12, 14-17 (2012
104. Gillmore, J. D., Lovat, L. B., Persey, M. R., Pepys, M. B., & Hawkins, P. N. Amyloid load, and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet 358, 24-29 (2001
105. Kisilevsky, R., Narindrasorasak, S., Tape, C., Tan, R., & Boudreau, L. During AA amyloidogenesis is proteolytic attack on serum amyloid A a pre-or post-fibrillogenic event? Amyloid 1, 174-183 (1994
106. Denis, M. A., et al. Control of AA amyloidosis complicating Crohn's disease: a clinico-pathological study. Eur. J. Clin. Invest. 43, 292-301 (2013
107. Ishii, W., et al A case with rheumatoid arthritis, and systemic reactive AA amyloidosis showing rapid regression of amyloid deposition on gastroduodenal mucosa after a combined therapy of corticosteroid, and etanercept. Rheumatol. Int. 31, 247-250 (2011
108. Kuroda, T., et al A case of AA amyloidosis associated with rheumatoid arthritis effectively treated with Infliximab. Rheumatol. Int. 28, 1155-1159 (2008
109. Lesnyak, Q., et al. Beneficial effect of eprodisate (NC 503) on the preservation of kidney function in AA amyloidosis patients: 3 year follow up results. Ann. Rheum. Dis. 66, 248-248 (2007
110. Matsuda, M., Morita, H., & Ikeda, S. Long-Term follow up of systemic reactive AA amyloidosis secondary to rheumatoid arthritis: successful treatment with intermediate-dose corticosteroid. Internal Med. 41, 403-407 (2002
111. Nakamura, T., et al. Efficacy of cyclophosphamide combined with prednisolone in patients with AA amyloidosis secondary to rheumatoid arthritis. Clin. Rheumatol. 22, 371-375 (2003
112. Srinivasan, S., et al. Pathogenic serum amyloid A1.1 shows a long oligomer-rich fibrillation lag phase contrary to the highly amyloidogenic non-pathogenic SAA2.2. J. Biol. Chem. 288, 2744-2755 (2013
113. Borchelt, D. R., et al. Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ1-42/1-40 ratio in vitro, and in vivo. Neuron 17, 1005-1013 (1996
114. Wolfe, M. S. Structure, mechanism, and inhibition of γ-secretase, and presenilin-like proteases. Biol. Chem. 391, 839-847 (2010
115. Sambamurti, K., et al. Targets for AD treatment: conflicting messages from γ-secretase inhibitors. J. Neurochem. 117, 359-374 (2011
116. De Strooper, B., Vassar, R., & Golde, T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat. Rev. Neurol. 6, 99-107 (2010
117. Yan, R., & Vassar, R. Targeting the β-secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol. 13, 319-329 (2014
118. Ghosh, A. K., & Osswald, H. L. BACE1 (â-secretase) inhibitors for the treatment of Alzheimer's disease. Chem. Soc. Rev. 43, 6765-6813 (2014
119. Ohno, M., et al. BACE1 deficiency rescues memory deficits, and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron 41, 27-33 (2004
120. De Strooper, B., Iwatsubo, T., & Wolfe, M. S. Presenilins, and γ-secretase: structure, function, and role in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2, a006304 (2012
121. De Strooper, B., & Gutierrez, L. C. Learning by failing: ideas, and concepts to tackle γ-secretases in Alzheimer disease, and beyond. Annu. Rev. Pharmacol. Toxicol. 55,419-437 (2014
122. Golde, T. E., Koo, E. H., Felsenstein, K. M., Osborne, B. A., & Miele, L. γ-secretase inhibitors, and modulators. Biochim. Biophys. Acta 1828, 2898-2907 (2013
123. Bard, F., et al. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system, and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916-919 (2000
124. Masliah, E., et al. Aβ vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64, 129-131 (2005
125. Coelho, T., et al. Safety, and efficacy of RNAi therapy for transthyretin amyloidosis. N. Engl. J. Med. 369, 819-829 (2013
126. Benson, M. D., et al. Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides. Muscle Nerve 33, 609-618 (2006
127. Zhou, P., Ma, X., Iyer, L., Chaulagain, C., & Comenzo, R. L. One siRNA pool targeting the ? constant region stops ? light-chain production, and causes terminal endoplasmic reticulum stress. Blood 123, 3440-3451 (2014
128. Hovey, B. M., et al. Preclinical development of siRNA therapeutics for AL amyloidosis. Gene Ther. 18, 1150-1156 (2011
129. Coelho, T., et al A strikingly benign evolution of FAP in an individual found to be a compound heterozygote for two TTR mutations: TTR MET 30, and TTR MET 119. J. Rheumatol. 20, 179 (1993
130. Johnson, S. M., et al. Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: a focus on the transthyretin amyloidoses. Acc. Chem. Res. 38, 911-921 (2005
131. Johnson, S. M., Connelly, S., Fearns, C., Powers, E. T., & Kelly, J. W. The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-Agency-Approved drug. J. Mol. Biol. 421, 185-203 (2012
132. Rappley, I., et al. Quantification of transthyretin kinetic stability in human plasma using subunit exchange. Biochemistry 53, 1993-2006 (2014
133. Miroy, G. J., et al. Inhibiting transthyretin amyloid fibril formation via protein stabilization. Proc. Natl Acad. Sci. USA 93, 15051-15056 (1996
134. Razavi, H., et al. Benzoxazoles as transthyretin amyloid fibril inhibitors: synthesis, evaluation, and mechanism of action. Angew. Chem. Int. Ed. Engl. 42, 2758-2761 (2003
135. Baures, P. W., Peterson, S. A., & Kelly, J. W. Discovering transthyretin amyloid fibril inhibitors by limited screening. Bioorg. Med. Chem. 6, 1389-1401 (1998
136. Klabunde, T., et al. Rational design of potent human transthyretin amyloid disease inhibitors. Nat. Struct. Biol. 7, 312-321 (2000
137. Connelly, S., Choi, S., Johnson, S. M., Kelly, J. W., & Wilson, I. A. Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses. Curr. Opin. Struct. Biol. 20, 54-62 (2010
138. Sekijima, Y., Dendle, M. A., & Kelly, J. W. Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid 13, 236-249 (2006
139. Tojo, K., Sekijima, Y., Kelly, J. W., & Ikeda, S. Diflunisal stabilizes familial amyloid polyneuropathy-Associated transthyretin variant tetramers in serum against dissociation required for amyloidogenesis. Neurosci. Res. 56, 441-449 (2006
140. Amaducci, L., & Tesco, G. Aging as a major risk for degenerative diseases of the central nervous system. Curr. Opin. Neurol. 7, 283-286 (1994
141. Ben-Zvi, A., Miller, E. A., & Morimoto, R. I. Collapse of proteostasis represents an early molecular event in Caenorhabditis elegans aging. Proc. Natl Acad. Sci. USA 106, 14914-14919 (2009
142. Gavilan, M. P., et al. Dysfunction of the unfolded protein response increases neurodegeneration in aged rat hippocampus following proteasome inhibition. Aging Cell 8, 654-665 (2009
143. Takeda, N., et al. Altered unfolded protein response is implicated in the age-related exacerbation of proteinuria-induced proximal tubular cell damage. Am. J. Pathol. 183, 774-785 (2013
144. Singh, R., et al. Reduced heat shock response in human mononuclear cells during aging, and its association with polymorphisms in HSP70 genes. Cell Stress Chaperones 11, 208-215 (2006
145. Gupta, R., et al. Firefly luciferase mutants as sensors of proteome stress. Nat. Methods 8, 879-884 (2011
146. Shoulders, M. D., et al. Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments. Cell Rep. 3, 1279-1292 (2013
147. Cooley, C. B., et al. Unfolded protein response activation reduces secretion, and extracellular aggregation of amyloidogenic immunoglobulin light chain. Proc. Natl Acad. Sci. USA 111, 13046-13051 (2014
148. Balch, W. E., Morimoto, R. I., Dillin, A., & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916-919 (2008
149. Powers, E. T., Morimoto, R. I., Dillin, A., Kelly, J. W., & Balch, W. E. Biological, and chemical approaches to diseases of proteostasis deficiency. Annu. Rev. Biochem. 78, 959-991 (2009
150. Mu, T. W., et al. Chemical, and biological approaches synergize to ameliorate protein-folding diseases. Cell 134, 769-781 (2008
151. Jinwal, U. K., et al. Imbalance of Hsp70 family variants fosters tau accumulation. FASEB J. 27, 1450-1459 (2013
152. Wang, A. M., et al. Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat. Chem. Biol. 9, 112-118 (2013
153. Craig, E. A. The heat-shock response. CRC Crit. Rev. Biochem. 18, 239-280 (1985
154. Lindquist, S. The heat-shock response. Annu. Rev. Biochem. 55, 1151-1191 (1986
155. Morimoto, R. I. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes Dev. 12, 3788-3796 (1998
156. Ron, D., & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519-529 (2007
157. Schroder, M., & Kaufman, R. J. The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739-789 (2005
158. Shoulders, M. D., Ryno, L. M., Cooley, C. B., Kelly, J. W., & Wiseman, R. L. Broadly applicable methodology for the rapid, and dosable small molecule-mediated regulation of transcription factors in human cells. J. Am. Chem. Soc. 135, 8129-8132 (2013
159. Calamini, B., et al. Small-molecule proteostasis regulators for protein conformational diseases. Nat. Chem. Biol. 8, 185-196 (2012
160. Zhang, Y. Q., & Sarge, K. D. Celastrol inhibits polyglutamine aggregation, and toxicity though induction of the heat shock response. J. Mol. Med. 85, 1421-1428 (2007
161. Bersuker, K., Hipp, M. S., Calamini, B., Morimoto, R. I., & Kopito, R. R. Heat shock response activation exacerbates inclusion body formation in a cellular model of Huntington disease. J. Biol. Chem. 288, 23633-23638 (2013
162. Sittler, A., et al. Geldanamycin activates a heat shock response, and inhibits huntingtin aggregation in a cell culture model of Huntington's disease. Hum. Mol. Genet. 10, 1307-1315 (2001
163. Aridon, P., et al. Protective role of heat shock proteins in Parkinson's disease. Neurodegener. Dis. 8, 155-168 (2011
164. Morley, J. F., & Morimoto, R. I. Regulation of longevity in Caenorhabditis elegans by heat shock factor, and molecular chaperones. Mol. Biol. Cell 15, 657-664 (2004
165. Warrick, J. M., et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat. Genet. 23, 425-428 (1999
166. Auluck, P. K., Chan, H. Y., Trojanowski, J. Q., Lee, V. M., & Bonini, N. M. Chaperone suppression of α-synuclein toxicity in a Drosophila model for Parkinson's disease. Science 295, 865-868 (2002
167. Shimshek, D. R., Mueller, M., Wiessner, C., Schweizer, T., & van der Putten, P. H. The HSP70 molecular chaperone is not beneficial in a mouse model of α-synucleinopathy. PLoS ONE 5, e10014 (2010
168. Pemberton, S., et al. Hsc70 protein interaction with soluble, and fibrillar α-synuclein. J. Biol. Chem. 286, 34690-34699 (2011
169. Danzer, K. M., et al. Heat-shock protein 70 modulates toxic extracellular α-synuclein oligomers, and rescues trans-synaptic toxicity. FASEB J. 25, 326-336 (2011
170. Hartl, F. U., Bracher, A., & Hayer-Hartl, M. Molecular chaperones in protein folding, and proteostasis. Nature 475, 324-332 (2011
171. Muchowski, P. J., et al. Hsp70, and Hsp40 chaperones can inhibit self-Assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl Acad. Sci. USA 97, 7841-7846 (2000
172. Mayer, M. P., et al. Multistep mechanism of substrate binding determines chaperone activity of Hsp70. Nat. Struct. Biol. 7, 586-593 (2000
173. Chafekar, S. M., et al. Pharmacological tuning of heat shock protein 70 modulates polyglutamine toxicity, and aggregation. ACS Chem. Biol. 7, 1556-1564 (2012
174. Abisambra, J., et al. Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau. Biol. Psychiatry 74, 367-374 (2013
175. Miyata, Y., et al. Synthesis, and initial evaluation of YM 08, a blood-brain barrier permeable derivative of the heat shock protein 70 (Hsp70) inhibitor MKT 077, which reduces tau levels. ACS Chem. Neurosci. 4, 930-939 (2013
176. Smith, M. C., et al. The E3 ubiquitin ligase CHIP, and the molecular chaperone Hsc70 form a dynamic, tethered complex. Biochemistry 52, 5354-5364 (2013
177. Genereux, J. C., et al. Unfolded protein response-induced ERdj3 secretion links ER stress to extracellular proteostasis. EMBO J. 34, e201488896 (2014
178. Villella, A. T., et al. Inhibition of Usp14 stimulates the proteolytic degradation, and clearance of misfolded proteins associated with neurodegenerative diseases. FASEB J. 27, lb131 (2013
179. Lee, B H., et Al. Enhancement of Proteasome Activity by A Small-molecule Inhibitor of USP14. Nature 467, 179-184 (2010
180. Kanemitsu, H., Tomiyama, T., & Mori, H. Human neprilysin is capable of degrading amyloid β peptide not only in the monomeric form but also the pathological oligomeric form. Neurosci. Lett. 350, 113-116 (2003
181. Leissring, M. A., et al. Enhanced proteolysis of β-Amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40, 1087-1093 (2003
182. Iwata, N., et al. Metabolic regulation of brain Aβ by neprilysin. Science 292, 1550-1552 (2001
183. Meilandt, W. J., et al. Neprilysin overexpression inhibits plaque formation but fails to reduce pathogenic Aβ oligomers, and associated cognitive deficits in human amyloid precursor protein transgenic mice. J. Neurosci. 29, 1977-1986 (2009
184. Planque, S. A., et al. Physiological IgM class catalytic antibodies selective for transthyretin amyloid. J. Biol. Chem. 289, 13243-13258 (2014
185. Nishiyama, Y., et al. Metal-dependent amyloid β-degrading catalytic antibody construct. J. Biotechnol. 180, 17-22 (2014
186. Miller, H. I., Rotman, Y., Benshaul, Y., & Ashkenaz, Y. The dissociation of amyloid filament to subunits. Israel J. Med. Sci. 4, 982-986 (1968
187. Safar, J., Roller, P. P., Gajdusek, D. C., & Gibbs, C. J. Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein. J. Biol. Chem. 268, 20276-20284 (1993
188. Hasegawa, K., Ono, K., Yamada, M., & Naiki, H. Kinetic modeling, and determination of reaction constants of Alzheimer's β-Amyloid fibril extension, and dissociation using surface plasmon resonance. Biochemistry 41, 13489-13498 (2002
189. Kristen, A. V., et al. Green tea halts progression of cardiac transthyretin amyloidosis: an observational report. Clin. Res. Cardiol. 101, 805-813 (2012
190. Bieschke, J., et al. EGCG remodels mature α-synuclein, and amyloid-β fibrils, and reduces cellular toxicity. Proc. Natl Acad. Sci. USA 107, 7710-7715 (2010
191. Ehrnhoefer, D. E., et al. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat. Struct. Mol. Biol. 15, 558-566 (2008
192. Meng, F., Abedini, A., Plesner, A., Verchere, C. B., & Raleigh, D. P. The flavanol (-)-epigallocatechin 3 gallate inhibits amyloid formation by islet amyloid polypeptide, disaggregates amyloid fibrils, and protects cultured cells against IAPP-induced toxicity. Biochemistry 49, 8127-8133 (2010
193. Cao, P., & Raleigh, D. P. Analysis of the inhibition, and remodeling of islet amyloid polypeptide amyloid fibers by flavanols. Biochemistry 51, 2670-2683 (2012
194. Young, L. M., Cao, P., Raleigh, D. P., Ashcroft, A. E., & Radford, S. E. Ion mobility spectrometry-mass spectrometry defines the oligomeric intermediates in amylin amyloid formation, and the mode of action of inhibitors. J. Am. Chem. Soc. 136, 660-670 (2014
195. Hyung, S. J., et al. Insights into antiamyloidogenic properties of the green tea extract (-)-epigallocatechin 3 gallate toward metal-Associated amyloid-β species. Proc. Natl Acad. Sci. USA 110, 3743-3748 (2013
196. Palhano, F. L., Lee, J., Grimster, N. P., & Kelly, J. W. Toward the molecular mechanism(s) by which EGCG treatment remodels mature amyloid fibrils. J. Am. Chem. Soc. 135, 7503-7510 (2013
197. Attar, A., Rahimi, F., & Bitan, G Modulators of amyloid protein aggregation, and toxicity: EGCG, and Clr01. Transl Neurosci. 4, 385-409 (2013
198. Lorenzen, N., et al. How epigallocatechin gallate can inhibit α-synuclein oligomer toxicity in vitro. J. Biol. Chem. 289, 21299-21310 (2014
199. Schenk, D., et al. Immunization with amyloid-β attenuates Alzheimer disease-like pathology in the PDAPP mouse. Nature 400, 173-177 (1999
200. Janus, C., et al. Aâ peptide immunization reduces behavioural impairment, and plaques in a model of Alzheimer's disease. Nature 408, 979-982 (2000
201. Morgan, D., et al. Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408, 982-985 (2000
202. Check, E. Nerve inflammation halts trial for Alzheimer's drug. Nature 415, 462 (2002
203. Nicoll, J. A., et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report. Nat. Med. 9, 448-452 (2003
204. Holmes, C., et al. Long-Term effects of Aβ42 immunisation in Alzheimer's disease: follow up of a randomised, placebo-controlled Phase I trial. Lancet 372, 216-223 (2008
205. Boche, D., et al. Consequence of Aâ immunization on the vasculature of human Alzheimer's disease brain. Brain 131, 3299-3310 (2008
206. Nicoll, J. A., et al. Aβ species removal after aβ42 immunization. J. Neuropathol. Exp. Neurol. 65, 1040-1048 (2006
207. DeMattos, R. B., et al. Peripheral anti Aβ antibody alters CNS, and plasma Aβ clearance, and decreases brain Aβ burden in a mouse model of Alzheimer's disease. Proc. Natl Acad. Sci. USA 98, 8850-8855 (2001
208. Wisniewski, T., & Goni, F. Immunotherapy for Alzheimer's disease. Biochem. Pharmacol. 88, 499-507 (2014
209. Bateman, R. J., et al. Clinical, and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367, 795-804 (2012
210. Masliah, E., et al. Passive immunization reduces behavioral, and neuropathological deficits in an α-synuclein transgenic model of Lewy body disease. PLoS ONE 6, e19338 (2011
211. Castillo-Carranza, D. L., et al. Passive immunization with tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J. Neurosci. 34, 4260-4272 (2014
212. Lindstrom, V., et al. Immunotherapy targeting α-synuclein protofibrils reduced pathology in (Thy 1)-h[A30P] α-synuclein mice. Neurobiol. Dis. 69, 134-143 (2014
213. Chai, X., et al. Passive immunization with anti-Tau antibodies in two transgenic models: reduction of tau pathology, and delay of disease progression. J. Biol. Chem. 286, 34457-34467 (2011
214. Masliah, E., et al. Effects of á-synuclein immunization in a mouse model of Parkinson's disease. Neuron 46, 857-868 (2005
215. Bae, E. J., et al. Antibody-Aided clearance of extracellular α-synuclein prevents cell to cell aggregate transmission. J. Neurosci. 32, 13454-13469 (2012
216. Doyle, S. M., & Wickner, S. Hsp104, and ClpB: protein disaggregating machines. Trends Biochem. Sci. 34, 40-48 (2009
217. Jackrel, M. E., et al. Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell 156, 170-182 (2014
218. Jackrel, M. E., & Shorter, J. Reversing deleterious protein aggregation with re engineered protein disaggregases. Cell Cycle 13, 1379-1383 (2014
219. Winkler, J., Tyedmers, J., Bukau, B., & Mogk, A. Chaperone networks in protein disaggregation, and prion propagation. J. Struct. Biol. 179, 152-160 (2012
220. Nixon, R. A. The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983-997 (2013
221. Hidvegi, T., et al. An autophagy-enhancing drug promotes degradation of mutant α1 antitrypsin Z, and reduces hepatic fibrosis. Science 329, 229-232 (2010
222. Harper, J. D., & Lansbury, P. T. Jr. Models of amyloid seeding in Alzheimer's disease, and scrapie: mechanistic truths, and physiological consequences of the time-dependent solubility of amyloid proteins. Annu. Rev. Biochem. 66, 385-407 (1997
223. Eisele, Y. S. From soluble Aβ to progressive Aβ aggregation: could prion-like templated misfolding play a role? Brain Pathol. 23, 333-341 (2013
224. Colby, D. W., & Prusiner, S. B. Prions. Cold Spring Harb. Perspect. Biol. 3, a006833 (2011
225. Irwin, D. J., et al. Evaluation of potential infectivity of Alzheimer, and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol. 70, 462-468 (2013
226. Johan, K., et al. Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils. Proc. Natl Acad. Sci. USA 95, 2558-2563 (1998
227. Kane, M. D., et al. Evidence for seeding of β-Amyloid by intracerebral infusion of Alzheimer brain extracts in β-Amyloid precursor protein-Transgenic mice. J. Neurosci. 20, 3606-3611 (2000
228. Meyer-Luehmann, M., et al. Exogenous induction of cerebral β-Amyloidogenesis is governed by agent, and host. Science 313, 1781-1784 (2006
229. Clavaguera, F., et al. Transmission, and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909-913 (2009
230. Mougenot, A. L., et al. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol. Aging 33, 2225-2228 (2012
231. Polymenidou, M., & Cleveland, D. W. Prion-like spread of protein aggregates in neurodegeneration. J. Exp. Med. 209, 889-893 (2012
232. Prusiner, S. B. Cell biology A unifying role for prions in neurodegenerative diseases. Science 336, 1511-1513 (2012
233. Ahmed, Z., et al A novel in vivo model of tau propagation with rapid, and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol. 127, 667-683 (2014
234. Eisele, Y. S., et al. Induction of cerebral β-Amyloidosis: intracerebral versus systemic Aβ inoculation. Proc. Natl Acad. Sci. USA 106, 12926-12931 (2009
235. Hamaguchi, T., et al. The presence of Aβ seeds, and not age per se, is critical to the initiation of Aβ deposition in the brain. Acta Neuropathol. 123, 31-37 (2012
236. Iba, M., et al. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's like tauopathy. J. Neurosci. 33, 1024-1037 (2013
237. Luk, K. C., et al. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J. Exp. Med. 209, 975-986 (2012
238. Zhou, J., Gennatas, E. D., Kramer, J. H., Miller, B. L., & Seeley, W. W. Predicting regional neurodegeneration from the healthy brain functional connectome. Neuron 73, 1216-1227 (2012
239. Ren, P. H., et al. Cytoplasmic penetration, and persistent infection of mammalian cells by polyglutamine aggregates. Nat. Cell Biol. 11, 219-225 (2009
240. Eleuteri, S., et al. Novel therapeutic strategy for neurodegeneration by blocking Aâ seeding mediated aggregation in models of Alzheimer's disease. Neurobiol. Dis. 74, 144-157 (2015
241. Yang, W., Dunlap, J. R., Andrews, R. B., & Wetzel, R. Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum. Mol. Genet. 11, 2905-2917 (2002
242. Eisele, Y. S., et al. Multiple factors contribute to the peripheral induction of cerebral β-Amyloidosis. J. Neurosci. 34, 10264-10273 (2014
243. Clavaguera, F., et al. Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol. 127, 299-301 (2014
244. Duran-Aniotz, C., et al. Aggregate-depleted brain fails to induce Aâ deposition in a mouse model of Alzheimer's disease. PLoS ONE 9, e89014 (2014
245. Stohr, J., et al. Purified, and synthetic Alzheimer's amyloid beta (Aβ) prions. Proc. Natl Acad. Sci. USA 109, 11025-11030 (2012
246. Zhang, Z., et al. De novo generation of infectious prions with bacterially expressed recombinant prion protein. FASEB J. 27, 4768-4775 (2013
247. Wang, F., Wang, X., Yuan, C. G., & Ma, J. Generating a prion with bacterially expressed recombinant prion protein. Science 327, 1132-1135 (2010
248. Guo, J. L., & Lee, V. M. Neurofibrillary tangle-like tau pathology induced by synthetic tau fibrils in primary neurons over-expressing mutant tau. FEBS Lett. 587, 717-723 (2013
249. Collinge, J., & Clarke, A. R A general model of prion strains, and their pathogenicity. Science 318, 930-936 (2007
250. Aguzzi, A., Heikenwalder, M., & Polymenidou, M. Insights into prion strains, and neurotoxicity. Nat. Rev. Mol. Cell Biol. 8, 552-561 (2007
251. Bessen, R. A., & Marsh, R. F. Biochemical, and physical properties of the prion protein from 2 strains of the transmissible mink encephalopathy agent. J. Virol. 66, 2096-2101 (1992
252. Casacciabonnefil, P., Kascsak, R. J., Fersko, R., Callahan, S., & Carp, R. I. Brain regional distribution of prion protein PrP27 30 in mice stereotaxically microinjected with different strains of scrapie. J. Infect. Dis. 167, 7-12 (1993
253. Dearmond, S. J., Yang, S. L., & Prusiner, S. B. The sites of PrP(Sc) deposition in the brain are prion strain-specific. J. Neuropathol. Exp. Neurol. 52, 293 (1993
254. Heilbronner, G., et al. Seeded strain-like transmission of β-Amyloid morphotypes in APP transgenic mice. EMBO Rep. 14, 1017-1022 (2013
255. Stohr, J., et al. Distinct synthetic Aβ prion strains producing different amyloid deposits in bigenic mice. Proc. Natl Acad. Sci. USA 111, 10329-10334 (2014
256. Watts, J. C., et al. Serial propagation of distinct strains of Aâ prions from Alzheimer's disease patients. Proc. Natl Acad. Sci. USA 111, 10323-10328 (2014
257. Sanders, D. W., et al. Distinct tau prion strains propagate in cells, and mice, and define different tauopathies. Neuron 82, 1271-1288 (2014
258. Clavaguera, F., et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl Acad. Sci. USA 110, 9535-9540 (2013
259. Guo, J. L., et al. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 154, 103-117 (2013
260. Bousset, L., et al. Structural, and functional characterization of two α-synuclein strains. Nat. Commun. 4, 2575 (2013
261. Langer, F., et al. Soluble Aβ seeds are potent inducers of cerebral β-Amyloid deposition. J. Neurosci. 31, 14488-14495 (2011
262. Jucker, M., & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45-51 (2013
263. Tsaytler, P., Harding, H. P., Ron, D., & Bertolotti, A. Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 332, 91-94 (2011
264. Cohen, A. S. Amyloidosis. N. Engl. J. Med. 277, 522-530 (1967
265. Hardy, J., & Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol. Sci. 12, 383-388 (1991
266. Selkoe, D. J. The molecular pathology of Alzheimer's disease. Neuron 6, 487-498 (1991
267. Hardy, J. A., & Higgins, G. A. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184-185 (1992
268. Holtzman, D. M., Morris, J. C., & Goate, A. M. Alzheimer's disease: the challenge of the second century. Sci. Transl Med. 3, 77sr1 (2011
269. Giannakopoulos, P., et al. Tangle, and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology 60, 1495-1500 (2003
270. Rowe, C. C., et al. Imaging β-Amyloid burden in aging, and dementia. Neurology 68, 1718-1725 (2007
271. Hardy, J., & Selkoe, D. J. The amyloid hypothesis of Alzheimer's disease: progress, and problems on the road to therapeutics. Science 297, 353-356 (2002
272. Walsh, D. M., & Selkoe, D. J. Aβ oligomers-A decade of discovery. J. Neurochem. 101, 1172-1184 (2007
273. Jack, C. R. Jr et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 9, 119-128 (2010
274. Blake, C. C., Geisow, M. J., Oatley, S. J., Rerat, B., & Rerat, C. Structure of prealbumin: secondary, tertiary, and quaternary interactions determined by Fourier refinement at 1.8 Å. J. Mol. Biol. 121, 339-356 (1978
275. Hornberg, A., Eneqvist, T., Olofsson, A., Lundgren, E., & Sauer-Eriksson, A. E A comparative analysis of 23 structures of the amyloidogenic protein transthyretin. J. Mol. Biol. 302, 649-669 (2000
276. Hamilton, J. A., & Benson, M. D. Transthyretin: a review from a structural perspective. Cell. Mol. Life Sci. 58, 1491-1521 (2001
277. Schneider, F., Hammarstrom, P., & Kelly, J. W. Transthyretin slowly exchanges subunits under physiological conditions: a convenient chromatographic method to study subunit exchange in oligomeric proteins. Protein Sci. 10, 1606-1613 (2001
278. Monaco, H. L., Rizzi, M., & Coda, A. Structure of a complex of two plasma proteins: transthyretin, and retinol-binding protein. Science 268, 1039-1041 (1995
279. Purkey, H. E., Dorrell, M. I., & Kelly, J. W. Evaluating the binding selectivity of transthyretin amyloid fibril inhibitors in blood plasma. Proc. Natl Acad. Sci. USA 98, 5566-5571 (2001
280. Saraiva, M. J. M. Transthyretin mutations in health, and disease. Hum. Mut. 5, 191-196 (1995
281. Sekijima, Y., et al. The biological, and chemical basis for tissue-selective amyloid disease. Cell 121, 73-85 (2005
282. Hammarstrom, P., Jiang, X., Hurshman, A. R., Powers, E. T., & Kelly, J. W. Sequence-dependent denaturation energetics: a major determinant in amyloid disease diversity. Proc. Natl Acad. Sci. USA 99 (Suppl. 4), 16427-16432 (2002
283. Lai, Z., Colon, W., & Kelly, J. W. The acid-mediated denaturation pathway of transthyretin yields a conformational intermediate that can self-Assemble into amyloid. Biochemistry 35, 6470-6482 (1996
284. Jiang, X., et al. An engineered transthyretin monomer that is nonamyloidogenic, unless it is partially denatured. Biochemistry 40, 11442-11452 (2001
285. Hurshman Babbes, A. R., Powers, E. T., & Kelly, J. W. Quantification of the thermodynamically linked quaternary, and tertiary structural stabilities of transthyretin, and its disease-Associated variants: the relationship between stability, and amyloidosis. Biochemistry 47, 6969-6984 (2008
286. Benson, M. D. Familial amyloidotic polyneuropathy. Trends Neurosci. 12, 88-92 (1989
287. Rapezzi, C., et al. Transthyretin-related amyloidoses, and the heart: a clinical overview. Nat. Rev. Cardiol. 7, 398-408 (2010
288. Dharmarajan, K., & Maurer, M. S. Transthyretin cardiac amyloidoses in older North Americans. J. Am. Geriatr. Soc. 60, 765-774 (2012
289. Miller, A. L., Falk, R. H., Levy, B. D., & Loscalzo, J A heavy heart. N. Engl. J. Med. 363, 1464-1470 (2010
290. Ng, B., Connors, L. H., Davidoff, R., Skinner, M., & Falk, R. H. Senile systemic amyloidosis presenting with heart failure: a comparison with light chain-Associated amyloidosis. Arch. Intern. Med. 165, 1425-1429 (2005
291. Vidal, R., et al. Meningocerebrovascular amyloidosis associated with a novel transthyretin mis-sense mutation at codon 18 (TTRD18G). Am. J. Pathol. 148, 361-366 (1996
292. Westermark, P., Sletten, K., Johansson, B., & Cornwell, G. G. 3rd. Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc. Natl Acad. Sci. USA 87, 2843-2845 (1990
293. Falk, R. H. Cardiac amyloidosis: a treatable disease, often overlooked. Circulation 124, 1079-1085 (2011
294. Hornstrup, L. S., Frikke-Schmidt, R., Nordestgaard, B. G., & Tybjaerg-Hansen, A. Genetic stabilization of transthyretin, cerebrovascular disease, and life expectancy. Arterioscler. Thromb. Vas. Biol. 33, 1441-1447 (2013
295. Kuroda, T., et al. Treatment with biologic agents improves the prognosis of patients with rheumatoid arthritis, and amyloidosis. J. Rheumatol. 39, 1348-1354 (2012
296. Nakamura, T., Higashi, S., Tomoda, K., Tsukano, M., & Baba, S. Efficacy of etanercept in patients with AA amyloidosis secondary to rheumatoid arthritis. Clin. Exp. Rheumatol. 25, 518-522 (2007
297. Hall, A., & Patel, T. R. in Progress in Medicinal Chemistry (eds Lawton, G., & Witty, D. R.) 101-145 (Elsevier, 2014
298. Kastritis, E., et al. Treatment of light chain (AL) amyloidosis with the combination of bortezomib, and dexamethasone. Haematologica 92, 1351-1358 (2007
299. Sitia, R., Palladini, G., & Merlini, G. Bortezomib in the treatment of AL amyloidosis: targeted therapy? Haematologica 92, 1302-1307 (2007
300. Holmgren, G., et al. Biochemical effect of liver transplantation in two Swedish patients with familial amyloidotic polyneuropathy (FAP met30). Clin. Genet. 40, 242-246 (1991
301. Benson, M. D., et al. Suppression of choroid plexus transthyretin levels by antisense oligonucleotide treatment. Amyloid 17, 43-49 (2010
302. DeTure, M., Hicks, C., & Petrucelli, L. Targeting heat shock proteins in tauopathies. Curr. Alzheimer Res. 7, 677-684 (2010
303. Herbst, M., & Wanker, E. E. Small molecule inducers of heat-shock response reduce polyQ-mediated huntingtin aggregation A possible therapeutic strategy. Neurodegener. Dis. 4, 254-260 (2007
304. Wang, Q., Guo, J., Jiao, P., Liu, H., & Yao, X. Exploring the influence of EGCG on the β-sheet-rich oligomers of human islet amyloid polypeptide (hIAPP1 37), and identifying its possible binding sites from molecular dynamics simulation. PLoS ONE 9, e94796 (2014
305. Schenk, D. Opinion: amyloid-β immunotherapy for Alzheimer's disease: the end of the beginning. Nat. Rev. Neurosci. 3, 824-828 (2002
306. Schenk, D. Hopes remain for an Alzheimer's vaccine. Nature 431, 398 (2004
307. Liu-Seifert, D., et al. Delayed-start analysis: Mild Alzheimer's disease patients in solanezumab trials, 3.5 years. Alzheimers Dement. (NY) http://dx. doi.org/10.1016/j.trci.2015.06.006 (2015