Key Points
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The misfolding and/or misassembly of more than 30 human proteins — for example, transthyretin, immunoglobulin light chain, serum amyloid A and amyloid-β — into various aggregate structures, a process known as amyloidogenesis, cause a range of degenerative disorders, collectively called amyloid diseases.
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Amyloidogenesis is a dynamic process; thus, the protein aggregates produced adopt a range of structures ranging from small, relatively unstructured oligomers to structurally well-defined cross-β-sheet amyloid fibrils. Some structures may only be produced in humans.
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Although there is mounting genetic and pharmacological evidence that the process of protein aggregation is an important driver of neurodegeneration, a structure–proteotoxicity relationship is lacking for all human amyloid diseases. Moreover, we do not understand how the process of aggregation leads to the loss of postmitotic tissue in any human amyloid disease.
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In this Review, we summarize current and emerging strategies to ameliorate degenerative disorders associated with protein aggregation, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates.
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Potential therapeutic strategies for degenerative disorders associated with protein aggregation include: protein stabilization to prevent the conformational changes that enable aggregation, protein reduction to lower the concentration of the aggregation-prone protein and thereby slow aggregation, aggregate clearance or remodelling to reduce proteotoxicity, cellular proteostasis network adaptation to enhance proteome quality control, and reducing seeding and cell-to-cell spreading.
Abstract
The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, which are collectively known as amyloid disorders. However, the mechanistic connection between the process of protein aggregation and tissue degeneration is not yet fully understood. Here, we review current and emerging strategies to ameliorate aggregation-associated degenerative disorders, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates. Persuasive pharmacological and genetic evidence now supports protein aggregation as the cause of postmitotic tissue dysfunction or loss. However, a more detailed understanding of the factors that trigger and sustain aggregate formation and of the structure–activity relationships underlying proteotoxicity is needed to develop future disease-modifying therapies.
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References
Andrade, C. A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain 75, 408–427 (1952).
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).
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).
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).
Sipe, J. D. et al. Nomenclature 2014: amyloid fibril proteins and clinical classification of the amyloidosis. Amyloid 21, 221–224 (2014).
Eisenberg, D. & Jucker, M. The amyloid state of proteins in human diseases. Cell 148, 1188–1203 (2012). In this review, the authors connect observations on amyloid polymorphism, amyloid strains and co-aggregation of pathogenic proteins in tissues to possible mechanisms of toxicity and intra-organismal transmissibility of amyloid disease.
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Eisele, Y. S. et al. Peripherally applied Aβ-containing inoculates induce cerebral β-amyloidosis. Science 330, 980–982 (2010). This paper shows that intraperitoneal inoculation with Aβ amyloid-rich extracts induced amyloidogenesis within the brains of transgenic mice after prolonged incubation times.
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).
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).
Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012). This manuscript demonstrates that a single intrastriatal inoculation of synthetic α-synuclein fibrils leads to the cell-to-cell transmission of pathological α-synuclein Parkinson-like Lewy pathology in anatomically interconnected regions. The pathology recapitulated the neurodegenerative cascade of Parkinson disease.
Tanzi, R. E. & Bertram, L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120, 545–555 (2005).
Coelho, T. et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology 79, 785–792 (2012). The data from a placebo-controlled double-blind clinical trial are summarized, demonstrating the efficacy of tafamidis in slowing the progression of TTR FAP in the efficacy-evaluable population.
Coelho, T. et al. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J. Neurol. 260, 2802–2814 (2013). This follow-on study demonstrates that the efficacy of tafamidis demonstrated in reference 22 is durable for an additional 18 months.
Berk, J. L. et al. Repurposing diflunisal for familial amyloid polyneuropathy a randomized clinical trial. JAMA 310, 2658–2667 (2013). The positive diflunisal clinical trial data provide complementary evidence that TTR kinetic stabilization is an effective therapeutic strategy.
Hammarstrom, P., Schneider, F. & Kelly, J. W. Trans-suppression of misfolding in an amyloid disease. Science 293, 2459–2462 (2001). This study demonstrates interallelic trans -suppression in an amyloid disease: the idea is that a disease-associated TTR mutation can be suppressed by a mutation within TTR on the second allele. This happens because TTR heterotetramer dissociation — the rate-limiting step of amyloidogenesis — is slowed dramatically, thus the concentration of misfolded monomers and aggregates is lower, and hence pathology is ameliorated.
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). This paper demonstrates how interallelic trans -suppression (reference 25), which relies on increasing the activation barrier for dissociation, can be mimicked by a small molecule that selectively binds to and stabilizes the native state during the dissociative transition state, thus slowing the rate-limiting step of amyloidogenesis. These small molecules are a special class of pharmacological chaperones called kinetic stabilizers.
Kastritis, E. et al. Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis. J. Clin. Oncol. 28, 1031–1037 (2010). This manuscript demonstrates that reducing LC concentration, and consequently its aggregation, by killing clonal plasma cells is efficacious for ameliorating AL amyloidosis.
Merlini, G., Comenzo, R. L., Seldin, D. C., Wechalekar, A. & Gertz, M. A. Immunoglobulin light chain amyloidosis. Expert Rev. Hematol. 7, 143–156 (2014).
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). This review introduces the range of non-amyloid aggregates and the basis for suspecting them as agents of proteotoxicity and postmitotic tissue loss.
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).
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). This paper introduces the preclinical data and rationale for using tafamidis as a kinetic stabilizer to ameliorate TTR amyloidoses.
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).
Colon, W. & Kelly, J. W. Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 31, 8654–8660 (1992). This paper demonstrates that conformational changes are sufficient to enable the process of amyloidogenesis.
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).
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).
Booth, D. R. et al. Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis. Nature 385, 787–793 (1997).
Dobson, C. M. Protein folding and misfolding. Nature 426, 884–890 (2003).
Dyson, H. J. & Wright, P. E. Intrinsically unstructured proteins and their functions. Nat. Rev. Mol. Cell Biol. 6, 197–208 (2005).
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).
De Strooper, B. et al. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522 (1999).
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).
Ross, C. A. Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders. Neuron 35, 819–822 (2002).
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).
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).
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).
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).
Kosik, K. S., Joachim, C. L. & Selkoe, D. J. MicrotubuIe-associated protein tau (τ) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc. Natl Acad. Sci. USA 83, 4044–4048 (1986).
Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).
Wolfe, M. S. Tau mutations in neurodegenerative diseases. J. Biol. Chem. 284, 6021–6025 (2009).
Drewes, G. et al. Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state. EMBO J. 11, 2131–2138 (1992).
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).
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).
Wang, L. et al. α-synuclein multimers cluster synaptic vesicles and attenuate recycling. Curr. Biol. 24, 2319–2326 (2014).
Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).
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).
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).
Olzscha, H. et al. Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144, 67–78 (2011).
Laganowsky, A. et al. Atomic view of a toxic amyloid small oligomer. Science 335, 1228–1231 (2012).
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). Reference 58 reports an oligomeric cylindrical barrel structure that is formed from six antiparallel strands of a segment of the amyloid-forming αB crystallin protein, which the authors call a cylindrin structure. This structure allows hypotheses about proteotoxicity of the type discussed in reference 59 to be generated and tested.
Ferrone, F. Analysis of protein aggregation kinetics. Methods Enzymol. 309, 256–274 (1999).
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).
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).
Serio, T. R. et al. Nucleated conformational conversion and the replication of conformational information by a prion determinant. Science 289, 1317–1321 (2000).
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).
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).
Lundmark, K. et al. Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc. Natl Acad. Sci. USA 99, 6979–6984 (2002). This pioneering paper demonstrated the acceleration of AA amyloidosis by the injection or oral administration of AA amyloid fibrils.
Aguzzi, A. & Rajendran, L. The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron 64, 783–790 (2009).
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).
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).
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).
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).
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). This manuscript demonstrates that a decrease in circulating soluble LC levels correlates with an improvement in health, without correlating with a decrease in LC amyloid fibrils.
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).
Winner, B. et al. In vivo demonstration that α-synuclein oligomers are toxic. Proc. Natl Acad. Sci. USA 108, 4194–4199 (2011).
Cohen, E., Bieschke, J., Perciavalle, R. M., Kelly, J. W. & Dillin, A. Opposing activities protect against age-onset proteotoxicity. Science 313, 1604–1610 (2006).
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).
Bieschke, J. et al. Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils. Nat. Chem. Biol. 8, 93–101 (2012). This paper demonstrates that the acceleration of Aβ fibrillogenesis, through the action of the orcein-related small molecule O4, decreases the concentration of small, toxic Aβ oligomers in aggregation reactions, as O4 treatment suppresses inhibition of long-term potentiation by Aβ oligomers in hippocampal brain slices.
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).
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).
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).
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).
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).
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).
Chartier-Harlin, M. C. et al. α-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167–1169 (2004).
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).
Holmgren, G. et al. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 341, 1113–1116 (1993). This pioneering approach of surgically mediated gene therapy for successfully treating TTR amyloid disease demonstrated the concept of protein reduction therapy.
Ihse, E. et al. Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis. J. Pathol. 216, 253–261 (2008).
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).
Yamashita, T. et al. Long-term survival after liver transplantation in patients with familial amyloid polyneuropathy. Neurology 78, 637–643 (2012).
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).
Delahaye, N. et al. Impact of liver transplantation on cardiac autonomic denervation in familial amyloid polyneuropathy. Medicine 85, 229–238 (2006).
Suhr, O. B. Impact of liver transplantation on familial amyloidotic polyneuropathy (FAP) patients' symptoms and complications. Amyloid 10, 77–83 (2003).
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).
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).
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).
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).
Maia, L. F. et al. CNS involvement in V30M transthyretin amyloidosis: clinical, neuropathological and biochemical findings. J. Neurol. Neurosurg. Psychiatry (2014).
Gertz, M. A. Immunoglobulin light chain amyloidosis: 2011 update on diagnosis, risk-stratification, and management. Am. J. Hematol. 86, 181–186 (2011).
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).
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).
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).
Comenzo, R. L. Current and emerging views and treatments of systemic immunoglobulin light-chain (AL) amyloidosis. Contrib. Nephrol. 153, 195–210 (2007).
Obici, L. & Merlini, G. Amyloidosis in autoinflammatory syndromes. Autoimmun. Rev. 12, 14–17 (2012).
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).
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).
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).
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).
Kuroda, T. et al. A case of AA amyloidosis associated with rheumatoid arthritis effectively treated with Infliximab. Rheumatol. Int. 28, 1155–1159 (2008).
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).
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). This work shows that a reduction in inflammation, which reduces the AA amyloidogenic protein concentration, is effective at ameliorating AA amyloidosis.
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).
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).
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).
Wolfe, M. S. Structure, mechanism and inhibition of γ-secretase and presenilin-like proteases. Biol. Chem. 391, 839–847 (2010).
Sambamurti, K. et al. Targets for AD treatment: conflicting messages from γ-secretase inhibitors. J. Neurochem. 117, 359–374 (2011).
De Strooper, B., Vassar, R. & Golde, T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat. Rev. Neurol. 6, 99–107 (2010).
Yan, R. & Vassar, R. Targeting the β-secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol. 13, 319–329 (2014). A few companies, including Merck, have developed BACE1-selective small-molecule inhibitors that hold great promise for ameliorating AD.
Ghosh, A. K. & Osswald, H. L. BACE1 (β-secretase) inhibitors for the treatment of Alzheimer's disease. Chem. Soc. Rev. 43, 6765–6813 (2014).
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).
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).
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).
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). The use of allosteric regulators of γ-secretase that impede Aβ generation without inhibiting its processing of critical substrates is an appealing strategy to ameliorate AD.
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).
Masliah, E. et al. Aβ vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology 64, 129–131 (2005). Amyloid disease vaccination in the absence of an immune or inflammatory reaction holds great promise for preventing the human amyloid diseases.
Coelho, T. et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N. Engl. J. Med. 369, 819–829 (2013).
Benson, M. D. et al. Targeted suppression of an amyloidogenic transthyretin with antisense oligonucleotides. Muscle Nerve 33, 609–618 (2006).
Zhou, P., Ma, X., Iyer, L., Chaulagain, C. & Comenzo, R. L. One siRNA pool targeting the λ constant region stops λ light-chain production and causes terminal endoplasmic reticulum stress. Blood 123, 3440–3451 (2014).
Hovey, B. M. et al. Preclinical development of siRNA therapeutics for AL amyloidosis. Gene Ther. 18, 1150–1156 (2011). References 125, 127 and 128 show that RNAi treatment is effective at reducing protein levels in some tissues and is a promising strategy for ameliorating amyloidosis in the systemic amyloidoses.
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).
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).
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). This review outlines the genetic and pharmacological evidence supporting the hypothesis that the process of TTR aggregation causes the TTR amyloidoses.
Rappley, I. et al. Quantification of transthyretin kinetic stability in human plasma using subunit exchange. Biochemistry 53, 1993–2006 (2014).
Miroy, G. J. et al. Inhibiting transthyretin amyloid fibril formation via protein stabilization. Proc. Natl Acad. Sci. USA 93, 15051–15056 (1996).
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).
Baures, P. W., Peterson, S. A. & Kelly, J. W. Discovering transthyretin amyloid fibril inhibitors by limited screening. Bioorg. Med. Chem. 6, 1389–1401 (1998).
Klabunde, T. et al. Rational design of potent human transthyretin amyloid disease inhibitors. Nat. Struct. Biol. 7, 312–321 (2000).
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).
Sekijima, Y., Dendle, M. A. & Kelly, J. W. Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid 13, 236–249 (2006).
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).
Amaducci, L. & Tesco, G. Aging as a major risk for degenerative diseases of the central nervous system. Curr. Opin. Neurol. 7, 283–286 (1994).
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).
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).
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).
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).
Gupta, R. et al. Firefly luciferase mutants as sensors of proteome stress. Nat. Methods 8, 879–884 (2011).
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). This paper demonstrates that UPR activation can lead to decreased secretion of amyloidogenic, but not WT, TTR.
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). Activation of the UPR stress-response signalling pathway transcriptionally reprogrammes the proteostasis network in the ER, enabling the detection and destruction of amyloidogenic, but not energetically normal, LCs.
Balch, W. E., Morimoto, R. I., Dillin, A. & Kelly, J. W. Adapting proteostasis for disease intervention. Science 319, 916–919 (2008).
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).
Mu, T. W. et al. Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell 134, 769–781 (2008).
Jinwal, U. K. et al. Imbalance of Hsp70 family variants fosters tau accumulation. FASEB J. 27, 1450–1459 (2013).
Wang, A. M. et al. Activation of Hsp70 reduces neurotoxicity by promoting polyglutamine protein degradation. Nat. Chem. Biol. 9, 112–118 (2013).
Craig, E. A. The heat-shock response. CRC Crit. Rev. Biochem. 18, 239–280 (1985).
Lindquist, S. The heat-shock response. Annu. Rev. Biochem. 55, 1151–1191 (1986).
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).
Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell Biol. 8, 519–529 (2007).
Schroder, M. & Kaufman, R. J. The mammalian unfolded protein response. Annu. Rev. Biochem. 74, 739–789 (2005).
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).
Calamini, B. et al. Small-molecule proteostasis regulators for protein conformational diseases. Nat. Chem. Biol. 8, 185–196 (2012).
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). The authors demonstrate that HSR activation, which transcriptionally reprogrammes the cytosolic proteostasis network, significantly decreases killing of cells expressing mutant polyQ proteins.
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).
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).
Aridon, P. et al. Protective role of heat shock proteins in Parkinson's disease. Neurodegener. Dis. 8, 155–168 (2011).
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).
Warrick, J. M. et al. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat. Genet. 23, 425–428 (1999).
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).
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).
Pemberton, S. et al. Hsc70 protein interaction with soluble and fibrillar α-synuclein. J. Biol. Chem. 286, 34690–34699 (2011).
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).
Hartl, F. U., Bracher, A. & Hayer-Hartl, M. Molecular chaperones in protein folding and proteostasis. Nature 475, 324–332 (2011).
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).
Mayer, M. P. et al. Multistep mechanism of substrate binding determines chaperone activity of Hsp70. Nat. Struct. Biol. 7, 586–593 (2000).
Chafekar, S. M. et al. Pharmacological tuning of heat shock protein 70 modulates polyglutamine toxicity and aggregation. ACS Chem. Biol. 7, 1556–1564 (2012).
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).
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).
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). In reference 174, the authors showed that nanomolar concentrations of the HSC70-modulating small molecule YM-01 administered to brain slices of tau transgenic mice were able to rapidly and potently reduce tau levels. These data, along with the data presented in reference 176, demonstrate that small molecules altering the HSP70–HSP40–nucleotide exchange factor pathway can affect amyloidogenic intrinsically disordered protein degradation.
Genereux, J. C. et al. Unfolded protein response-induced ERdj3 secretion links ER stress to extracellular proteostasis. EMBO J. 34, e201488896 (2014).
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).
Lee, B. H. et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature 467, 179–184 (2010). This paper shows that inhibition of DUBs has the potential to reduce the concentration of amyloidogenic proteins via enhanced proteasome degradation of misfolded, ubiquitylated proteins.
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).
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).
Iwata, N. et al. Metabolic regulation of brain Aβ by neprilysin. Science 292, 1550–1552 (2001).
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).
Planque, S. A. et al. Physiological IgM class catalytic antibodies selective for transthyretin amyloid. J. Biol. Chem. 289, 13243–13258 (2014).
Nishiyama, Y. et al. Metal-dependent amyloid β-degrading catalytic antibody construct. J. Biotechnol. 180, 17–22 (2014).
Miller, H. I., Rotman, Y., Benshaul, Y. & Ashkenaz, Y. The dissociation of amyloid filament to subunits. Israel J. Med. Sci. 4, 982–986 (1968).
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).
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).
Kristen, A. V. et al. Green tea halts progression of cardiac transthyretin amyloidosis: an observational report. Clin. Res. Cardiol. 101, 805–813 (2012).
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).
Ehrnhoefer, D. E. et al. EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers. Nat. Struct. Mol. Biol. 15, 558–566 (2008).
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).
Cao, P. & Raleigh, D. P. Analysis of the inhibition and remodeling of islet amyloid polypeptide amyloid fibers by flavanols. Biochemistry 51, 2670–2683 (2012).
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).
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).
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).
Attar, A., Rahimi, F. & Bitan, G. Modulators of amyloid protein aggregation and toxicity: EGCG and Clr01. Transl Neurosci. 4, 385–409 (2013).
Lorenzen, N. et al. How epigallocatechin gallate can inhibit α-synuclein oligomer toxicity in vitro. J. Biol. Chem. 289, 21299–21310 (2014).
Schenk, D. et al. Immunization with amyloid-β attenuates Alzheimer disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999). References 191–199 demonstrate that aggregate-remodelling small molecules could be useful for ameliorating amyloid diseases, as indicated by a clinical report outlined in reference 190.
Janus, C. et al. Aβ peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature 408, 979–982 (2000).
Morgan, D. et al. Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature 408, 982–985 (2000).
Check, E. Nerve inflammation halts trial for Alzheimer's drug. Nature 415, 462 (2002).
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).
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).
Boche, D. et al. Consequence of Aβ immunization on the vasculature of human Alzheimer's disease brain. Brain 131, 3299–3310 (2008).
Nicoll, J. A. et al. Aβ species removal after aβ42 immunization. J. Neuropathol. Exp. Neurol. 65, 1040–1048 (2006).
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).
Wisniewski, T. & Goni, F. Immunotherapy for Alzheimer's disease. Biochem. Pharmacol. 88, 499–507 (2014).
Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367, 795–804 (2012).
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).
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).
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).
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).
Masliah, E. et al. Effects of α-synuclein immunization in a mouse model of Parkinson's disease. Neuron 46, 857–868 (2005).
Bae, E. J. et al. Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J. Neurosci. 32, 13454–13469 (2012).
Doyle, S. M. & Wickner, S. Hsp104 and ClpB: protein disaggregating machines. Trends Biochem. Sci. 34, 40–48 (2009).
Jackrel, M. E. et al. Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell 156, 170–182 (2014).
Jackrel, M. E. & Shorter, J. Reversing deleterious protein aggregation with re-engineered protein disaggregases. Cell Cycle 13, 1379–1383 (2014).
Winkler, J., Tyedmers, J., Bukau, B. & Mogk, A. Chaperone networks in protein disaggregation and prion propagation. J. Struct. Biol. 179, 152–160 (2012).
Nixon, R. A. The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983–997 (2013).
Hidvegi, T. et al. An autophagy-enhancing drug promotes degradation of mutant α1-antitrypsin Z and reduces hepatic fibrosis. Science 329, 229–232 (2010).
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).
Eisele, Y. S. From soluble Aβ to progressive Aβ aggregation: could prion-like templated misfolding play a role? Brain Pathol. 23, 333–341 (2013).
Colby, D. W. & Prusiner, S. B. Prions. Cold Spring Harb. Perspect. Biol. 3, a006833 (2011).
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).
Johan, K. et al. Acceleration of amyloid protein A amyloidosis by amyloid-like synthetic fibrils. Proc. Natl Acad. Sci. USA 95, 2558–2563 (1998).
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).
Meyer-Luehmann, M. et al. Exogenous induction of cerebral β-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006). This paper demonstrates that intracerebral injection of Aβ amyloid-containing brain extracts can induce cerebral Aβ amyloidogenesis in mice. The phenotype of amyloidosis depends on both the host and the source of the agent, suggesting the existence of polymorphic Aβ strains, indicative of prion strains. This paper and others make the case that reducing anatomical spreading would probably be an efficacious therapeutic strategy.
Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009).
Mougenot, A. L. et al. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol. Aging 33, 2225–2228 (2012).
Polymenidou, M. & Cleveland, D. W. Prion-like spread of protein aggregates in neurodegeneration. J. Exp. Med. 209, 889–893 (2012).
Prusiner, S. B. Cell biology. A unifying role for prions in neurodegenerative diseases. Science 336, 1511–1513 (2012).
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).
Eisele, Y. S. et al. Induction of cerebral β-amyloidosis: intracerebral versus systemic Aβ inoculation. Proc. Natl Acad. Sci. USA 106, 12926–12931 (2009).
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).
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).
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).
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).
Ren, P. H. et al. Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates. Nat. Cell Biol. 11, 219–225 (2009).
Eleuteri, S. et al. Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease. Neurobiol. Dis. 74, 144–157 (2015).
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).
Eisele, Y. S. et al. Multiple factors contribute to the peripheral induction of cerebral β-amyloidosis. J. Neurosci. 34, 10264–10273 (2014).
Clavaguera, F. et al. Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol. 127, 299–301 (2014).
Duran-Aniotz, C. et al. Aggregate-depleted brain fails to induce Aβ deposition in a mouse model of Alzheimer's disease. PLoS ONE 9, e89014 (2014).
Stohr, J. et al. Purified and synthetic Alzheimer's amyloid beta (Aβ) prions. Proc. Natl Acad. Sci. USA 109, 11025–11030 (2012).
Zhang, Z. et al. De novo generation of infectious prions with bacterially expressed recombinant prion protein. FASEB J. 27, 4768–4775 (2013).
Wang, F., Wang, X., Yuan, C. G. & Ma, J. Generating a prion with bacterially expressed recombinant prion protein. Science 327, 1132–1135 (2010).
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).
Collinge, J. & Clarke, A. R. A general model of prion strains and their pathogenicity. Science 318, 930–936 (2007).
Aguzzi, A., Heikenwalder, M. & Polymenidou, M. Insights into prion strains and neurotoxicity. Nat. Rev. Mol. Cell Biol. 8, 552–561 (2007).
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).
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).
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).
Heilbronner, G. et al. Seeded strain-like transmission of β-amyloid morphotypes in APP transgenic mice. EMBO Rep. 14, 1017–1022 (2013).
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).
Watts, J. C. et al. Serial propagation of distinct strains of Aβ prions from Alzheimer's disease patients. Proc. Natl Acad. Sci. USA 111, 10323–10328 (2014).
Sanders, D. W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).
Clavaguera, F. et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl Acad. Sci. USA 110, 9535–9540 (2013).
Guo, J. L. et al. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 154, 103–117 (2013).
Bousset, L. et al. Structural and functional characterization of two α-synuclein strains. Nat. Commun. 4, 2575 (2013).
Langer, F. et al. Soluble Aβ seeds are potent inducers of cerebral β-amyloid deposition. J. Neurosci. 31, 14488–14495 (2011).
Jucker, M. & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51 (2013).
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).
Cohen, A. S. Amyloidosis. N. Engl. J. Med. 277, 522–530 (1967).
Hardy, J. & Allsop, D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol. Sci. 12, 383–388 (1991).
Selkoe, D. J. The molecular pathology of Alzheimer's disease. Neuron 6, 487–498 (1991).
Hardy, J. A. & Higgins, G. A. Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).
Holtzman, D. M., Morris, J. C. & Goate, A. M. Alzheimer's disease: the challenge of the second century. Sci. Transl Med. 3, 77sr1 (2011).
Giannakopoulos, P. et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer's disease. Neurology 60, 1495–1500 (2003).
Rowe, C. C. et al. Imaging β-amyloid burden in aging and dementia. Neurology 68, 1718–1725 (2007).
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).
Walsh, D. M. & Selkoe, D. J. Aβ oligomers — a decade of discovery. J. Neurochem. 101, 1172–1184 (2007).
Jack, C. R. Jr et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 9, 119–128 (2010).
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).
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).
Hamilton, J. A. & Benson, M. D. Transthyretin: a review from a structural perspective. Cell. Mol. Life Sci. 58, 1491–1521 (2001).
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).
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).
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).
Saraiva, M. J. M. Transthyretin mutations in health and disease. Hum. Mut. 5, 191–196 (1995).
Sekijima, Y. et al. The biological and chemical basis for tissue-selective amyloid disease. Cell 121, 73–85 (2005).
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).
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).
Jiang, X. et al. An engineered transthyretin monomer that is nonamyloidogenic, unless it is partially denatured. Biochemistry 40, 11442–11452 (2001).
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).
Benson, M. D. Familial amyloidotic polyneuropathy. Trends Neurosci. 12, 88–92 (1989).
Rapezzi, C. et al. Transthyretin-related amyloidoses and the heart: a clinical overview. Nat. Rev. Cardiol. 7, 398–408 (2010).
Dharmarajan, K. & Maurer, M. S. Transthyretin cardiac amyloidoses in older North Americans. J. Am. Geriatr. Soc. 60, 765–774 (2012).
Miller, A. L., Falk, R. H., Levy, B. D. & Loscalzo, J. A heavy heart. N. Engl. J. Med. 363, 1464–1470 (2010).
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).
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).
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).
Falk, R. H. Cardiac amyloidosis: a treatable disease, often overlooked. Circulation 124, 1079–1085 (2011).
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).
Kuroda, T. et al. Treatment with biologic agents improves the prognosis of patients with rheumatoid arthritis and amyloidosis. J. Rheumatol. 39, 1348–1354 (2012).
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).
Hall, A. & Patel, T. R. in Progress in Medicinal Chemistry (eds Lawton, G. & Witty, D. R.) 101–145 (Elsevier, 2014).
Kastritis, E. et al. Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone. Haematologica 92, 1351–1358 (2007).
Sitia, R., Palladini, G. & Merlini, G. Bortezomib in the treatment of AL amyloidosis: targeted therapy? Haematologica 92, 1302–1307 (2007).
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).
Benson, M. D. et al. Suppression of choroid plexus transthyretin levels by antisense oligonucleotide treatment. Amyloid 17, 43–49 (2010).
DeTure, M., Hicks, C. & Petrucelli, L. Targeting heat shock proteins in tauopathies. Curr. Alzheimer Res. 7, 677–684 (2010).
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).
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).
Schenk, D. Opinion: amyloid-β immunotherapy for Alzheimer's disease: the end of the beginning. Nat. Rev. Neurosci. 3, 824–828 (2002).
Schenk, D. Hopes remain for an Alzheimer's vaccine. Nature 431, 398 (2004).
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).
Acknowledgements
The authors thank the reviewers for their critical and insightful comments that shaped their thinking and helped to improve the manuscript. Y.S.E. expresses particular thanks to M. Jucker, Tübingen, Germany, for helpful discussions and for his mentorship. The authors are supported by US National Institutes of Health grants DK46335 (to J.W.K.), AG46495 (to J.W.K.) and GM101644 (to E.T.P.). Y.S.E. is supported by a postdoctoral fellowship from the German Academic Exchange Service (DAAD). The authors apologize to colleagues whose work they were unable to include owing to space limitations.
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J.W.K. and E.T.P. discovered tafamidis, and J.W.K. founded FoldRx to commercialize it. FoldRx is now owned by Pfizer, in which both J.W.K. and E.T.P. have a financial interest. J.W.K. is a shareholder and a paid consultant for Pfizer, which sells tafamidis. J.W.K. and E.T.P. receive royalty payments from the sale of tafamidis. Y.S.E., C.M., C.F., S.E.E. and R.L.W. declare no competing financial interests.
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DATABASES
Glossary
- Amyloid fibrils
-
Lateral assemblies of protein aggregates adopting a cross-β-sheet structure. These aggregates bind to Congo red, thioflavin T and analogous aromatics.
- Amyloidogenesis
-
The process of protein aggregation in an organism whereby physical chemical forces and biological modifiers together influence the aggregate structural ensembles afforded.
- Proteostasis network
-
The macromolecular machinery that generates, folds, moves and degrades the proteome. Proteostasis network components include chaperones, the proteasome, trafficking machinery and various enzymes — such as disulfide isomerases — that act on the proteome.
- Nucleus
-
An energetically unfavourable, sparsely populated, typically oligomeric species that is thought to be rich in β-sheet structure. Nucleus formation is the rate-limiting step for efficient aggregation in a nucleation-dependent polymerization; it is followed by rapid monomer addition, which produces a seed.
- Seeds
-
Stable aggregates that result from the addition of monomers to a nucleus or that arise from the fragmentation of fibrils. Seeds enable homotypic protein aggregation without a requirement for nucleus formation, as seeded aggregation bypasses the requirement for a nucleation step.
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Eisele, Y., Monteiro, C., Fearns, C. et al. Targeting protein aggregation for the treatment of degenerative diseases. Nat Rev Drug Discov 14, 759–780 (2015). https://doi.org/10.1038/nrd4593
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DOI: https://doi.org/10.1038/nrd4593
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