685
Views
7
CrossRef citations to date
0
Altmetric
Review Article

Protein misfolding, ER stress and chaperones: an approach to develop chaperone-based therapeutics for Alzheimer’s disease

, , &
Pages 714-734 | Received 30 Jan 2021, Accepted 08 Aug 2021, Published online: 21 May 2022

References

  • Zhou W, Bercury K, Cummiskey J, et al. Phenylbutyrate up-regulates the DJ-1 protein and protects neurons in cell culture and in animal models of Parkinson disease. J Biol Chem. 2011;286(17):14941–14951.
  • Cuadrado-Tejedor M, Ricobaraza AL, Torrijo R, et al. Rafael franco AG-O. Phenylbutyrate is a multifaceted drug that exerts neuroprotective effects and reverses the Alzheimer’s disease-like phenotype of a commonly used mouse model. Curr Pharm Des. 2013;19(28):5076–5084.
  • Bhardwaj A, Bhardwaj R, Dhawan DK, et al. Exploring the effect of endoplasmic reticulum stress inhibition by 4-phenylbutyric acid on AMPA-induced hippocampal excitotoxicity in rat brain. Neurotox Res. 2019;35(1):83–91.
  • Balch WE, Morimoto RI, Dillin A, et al. Adapting proteostasis for disease intervention. Science. 2008;319(5865):916–919.
  • Balchin D, Hayer-Hartl M, Hartl FU. In vivo aspects of protein folding and quality control. Science. 2016;353(6294):aac4354–aac4354.
  • Herczenik E, Gebbink MFBG. Molecular and cellular aspects of protein misfolding and disease. Faseb J. 2008;22(7):2115–2133.
  • Valastyan JS, Lindquist S. Mechanisms of protein-folding diseases at a glance. Dis Model Mech. 2014;7(1):9–14.
  • Lim J, Yue Z. Neuronal aggregates: formation, clearance, and spreading. Dev Cell. 2015;32(4):491–501.
  • Shacham T, Sharma N, Lederkremer GZ. Protein misfolding and ER stress in Huntington’s disease. Front Mol Biosci. 2019;6(APR):20.
  • Chen GF, Xu TH, Yan Y, et al. Amyloid beta: structure, biology and structure-based therapeutic development. Acta Pharmacol Sin. 2017;38(9):1205–1235. http://dx.doi.org/10.1038/aps.2017.28
  • Parakh S, Atkin JD. Protein folding alterations in amyotrophic lateral sclerosis. Brain Res. 2016;1648:633–649.
  • Tan JMM, Wong ESP, Lim KL . Protein misfolding and aggregation in Parkinson’s disease. Antioxid Redox Signal. 2009;11(9):2119–2134.
  • Sweeney P, Park H, Baumann M, et al. Protein misfolding in neurodegenerative diseases: implications and strategies. Transl Neurodegener. 2017;6(1):6–13.
  • Pedersen JT, Heegaard NHH. Analysis of protein aggregation in neurodegenerative disease. Anal Chem. 2013;85(9):4215–4227.
  • Soto C, Estrada LD. Protein misfolding and neurodegeneration. Arch Neurol. 2008;65(2):184–189.
  • Soto C, Estrada L, Castilla J. Amyloids, prions and the inherent infectious nature of misfolded protein aggregates. Trends Biochem Sci. 2006;31(3):150–155.
  • Selkoe, Dennis J. Alzheimer ‘ s disease : genes, proteins, and therapy. Physiol Rev. 2001;81(2):741–766.
  • DeTure MA, Dickson DW. The neuropathological diagnosis of Alzheimer’s disease. Mol Neurodegener. [Internet]. 2019;14(1):32. doi:.
  • Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J Biol Chem. 2008;283(44):29615–29619.
  • Bitan G, Kirkitadze MD, Lomakin A, et al . Amyloid beta -protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways . Proc Natl Acad Sci U S A. 2003;100(1):330–335.
  • De-Paula VJ, Radanovic M, Diniz BS, et al. Alzheimer’s disease. Subcellular Biochemistry. 2012;65:329–352.
  • Lublin AL, Gandy S . Amyloid-beta oligomers: possible roles as key neurotoxins in Alzheimer’s disease. Mt Sinai J Med. 2010;77(1):43–49.
  • Hsu F, Park G, Guo Z. Key residues for the formation of Aβ42 amyloid fibrils. ACS Omega. 2018;3(7):8401–8407.
  • Yan Y, Wang C . Aβ42 is more rigid than Aβ40 at the C terminus: implications for Aβ aggregation and toxicity. J Mol Biol. 2006;364(5):853–862.
  • Giannakopoulos P, Herrmann FR, Bussière T, et al . Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology. 2003;60(9):1495–1500.
  • Barbier P, Zejneli O, Martinho M, et al. Role of tau as a microtubule-associated protein: structural and functional aspects. Front Aging Neurosci. 2019;10(JUL):1–14.
  • Korolev IO. Alzheimer ‘s disease: a clinical and basic science review. Med Student Res J. 2014;04:24–33.
  • Imahori K . The biochemical study on the etiology of Alzheimer’s disease. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(1):54–61. https://pubmed.ncbi.nlm.nih.gov/20075608
  • Šimić G, Babić Leko M, Wray S, et al. Tau protein hyperphosphorylation and aggregation in Alzheimer’s disease and other tauopathies, and possible neuroprotective strategies. Biomolecules. 2016;6(1):6. https://pubmed.ncbi.nlm.nih.gov/26751493
  • Fitzpatrick AW, Falcon1 B, He S, SHWS, et al. Cryo-EM structures of tau filaments from Alzheimer’s disease brain. Physiol Behav. 2017;176(3):139–148.
  • Gong C-X, Iqbal K. Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr Med Chem. 2008;15(23):2321–2328. https://pubmed.ncbi.nlm.nih.gov/18855662
  • Bellucci M, De Marchis F, Pompa A. The endoplasmic reticulum is a hub to sort proteins toward unconventional traffic pathways and endosymbiotic organelles. J Exp Bot. 2017; 69(1):7–20.
  • Jan CH, Williams CC, Weissman JS. Principles of ER cotranslational translocation revealed by proximity-specific ribosome profiling. Science. 2014;346(6210):1217.
  • Reid DW, Nicchitta CV. Diversity and selectivity in mRNA translation on the endoplasmic reticulum. Nat Rev Mol Cell Biol. 2015;16(4):221–231. http://dx.doi.org/10.1038/nrm3958
  • Chambers JE, Marciniak SJ. Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 2. Protein misfolding and ER stress. Am J Physiol Cell Physiol. 2014;307(8):C657–70.
  • Braakman I, Bulleid NJ. Protein folding and modification in the mammalian endoplasmic reticulum. Annu Rev Biochem. 2011;80(1):71–99.
  • Braakman I, Hebert DN. Protein folding in the endoplasmic reticulum. Cold Spring Harb Perspect Biol. 2013;5(5):a013201.
  • Zhu G, lee A. Role of the unfolded protein response, GRP78 and GRP94 in organ homeostasis. Physiol  Behav. 2017;176(3):139–148.
  • Ruggiano A, Foresti O, Carvalho P . Quality control: ER-associated degradation: protein quality control and beyond. J Cell Biol. 2014;204(6):869–879.
  • Sitia R, Braakman I. Quality control in the endoplasmic reticulum protein factory. Nature. 2003;426(6968):891–894.
  • Ma Y, Hendershot LM. The mammalian endoplasmic reticulum as a sensor for cellular stress. Cell Stress Chaper. 2002;7(2):222–229.
  • Rutkowski DT, Kaufman RJ. A trip to the ER: coping with stress. Trends Cell Biol. 2004;14(1):20–28.
  • Kopito RR. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol. 2000;10(12):524–530.
  • Harding HP, Calfon M, Urano F, et al. Transcriptional and translational control in the mammalian unfolded protein response. Annu Rev Cell Dev Biol. 2002;18(1):575–599.
  • Harding HP, Ron D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes. 2002;51(suppl_3):S455–S61.
  • Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 2011;13(3):184–190. http://dx.doi.org/10.1038/ncb0311-184
  • Shapiro1 DJ, Livezey1 M, Yu1 L, et al. Anticipatory UPR activation: a protective pathway and target in cancer. Physiol Behav. 2017;176(10):139–148. file:///C:/Users/CarlaCarolina/Desktop/Artigosparaacrescentarnaqualificação/Theimpactofbirthweightoncardiovasculardisease_riskinthe.pdf
  • Szegezdi E, Logue SE, Gorman AM, et al. Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 2006;7(9):880–885.
  • Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519–529.
  • Chen X, Shen J, Prywes R. The luminal domain of ATF6 senses endoplasmic reticulum (ER) stress and causes translocation of ATF6 from the ER to the Golgi. J Biol Chem. 2002;277(15):13045–13052.
  • Ye J, Rawson RB, Komuro R, et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell. 2000;6(6):1355–1364.
  • Yoshida H, Matsui T, Yamamoto A, et al. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107(7):881–891.
  • Calfon M, Zeng H, Urano F, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature. 2002;415(6867):92–96.
  • Lee K, Tirasophon W, Shen X, et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev. 2002;16(4):452–466.
  • Rao RV, Bredesen DE. Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Curr Opin Cell Biol. 2004;16(6):653–662.
  • Ron D. Translational control in the endoplasmic reticulum stress response. J Clin Invest. 2002;110(10):1383–1388.
  • Bertolotti A, Zhang Y, Hendershot LM, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded- protein response. Nat Cell Biol. 2000;2:1–7. papers://2da1dc00-8ef8-49ed-93f8-79080a9217f1/Paper/p540
  • Lindholm D, Wootz H, Korhonen L. ER stress and neurodegenerative diseases. Cell Death Differ. 2006;13(3):385–392.
  • Díaz-Villanueva JF, Díaz-Molina R, García-González V. Protein folding and mechanisms of proteostasis. Int J Mol Sci. 2015;16(8):17193–17230. https://pubmed.ncbi.nlm.nih.gov/26225966
  • Kozutsumi Y, Segal M, Normington K, et al. The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature. 1988;332(6163):462–464.
  • Wilquet V, Strooper BD. Amyloid-beta precursor protein processing in neurodegeneration. Curr Opin Neurobiol. 2004;14(5):582–588.
  • Laferla F . Calcium dyshomeostasis and intracellular signalling in Alzheimer’s disease. Nat Rev Neurosci. 2002;3(11):862–872.
  • Kadowaki H, Nishitoh H, Urano F, et al . Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation . Cell Death Differ. 2005;12(1):19–24.
  • Viana RJS, Nunes AF, Rodrigues CMP . Endoplasmic reticulum enrollment in Alzheimer’s disease. Mol Neurobiol. 2012;46(2):522–534.
  • Hoozemans JJM, Veerhuis R, Van Haastert ES, et al . The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol. 2005;110(2):165–172.
  • O’Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci. 2011;34(1):185–204. https://pubmed.ncbi.nlm.nih.gov/21456963
  • Haass C, Kaether C, Thinakaran G, et al. Trafficking and proteolytic processing of APP. Cold Spring Harb Perspect Med. 2012;2(5):1–25.
  • LaFerla FM, Green KN, Oddo S . Intracellular amyloid-beta in Alzheimer’s disease . Nat Rev Neurosci. 2007;8(7):499–509.
  • Groemer TW, Thiel CS, Holt M, et al. Amyloid precursor protein is trafficked and secreted via synaptic vesicles. PLoS One. [2011;6(4):e18754.
  • Kaether C, Schmitt S, Willem M, et al. Amyloid precursor protein and notch intracellular domains are generated after transport of their precursors to the cell surface. Traffic. 2006;7(4):408–415.
  • Hoozemans JJM, Van Haastert ES, Nijholt DAT, et al . The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol. 2009;174(4):1241–1251. http://dx.doi.org/10.2353/ajpath.2009.080814
  • Resende R, Ferreiro E, Pereira C, et al . ER stress is involved in Aβ-induced GSK-3β activation and tau phosphorylation . J Neurosci Res. 2008;86(9):2091–2099.
  • Bogoyevitch MA, Kobe B. Uses for JNK: the many and varied substrates of the c-Jun N-Terminal kinases. Microbiol Mol Biol Rev. 2006;70(4):1061–1095.
  • Dhanasekaran DN, Reddy EP. JNK signaling in apoptosis. Oncogene. 2008;27(48):6245–6251.
  • Sekine Y, Takeda K, Ichijo H. The ASK1-MAP kinase signaling in ER stress and neurodegenerative diseases. Curr Mol Med. 2006;6(1):87–97.
  • Salminen A, Kauppinen A, Suuronen T, et al. ER stress in Alzheimer’s disease: a novel neuronal trigger for inflammation and Alzheimer’s pathology. J Neuroinflammation. 2009;6:41–13.
  • Urano F, Wang XZ, Bertolotti A, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000;287(5453):664–666.
  • Okazawa H, Estus S. The JNK/c-Jun Cascade and Alzheimer ‘ s disease. Am J Alzheimers Dis Other Demen. 2002;17(2):79–88.
  • Colombo A, Bastone A, Ploia C, et al . JNK regulates APP cleavage and degradation in a model of Alzheimer’s disease. Neurobiol Dis. 2009;33(3):518–525. http://dx.doi.org/10.1016/j.nbd.2008.12.014
  • Colombo A, Repici M, Pesaresi M, et al. The TAT-JNK inhibitor peptide interferes with beta amyloid protein stability. Cell Death Differ. 2007;14(10):1845–1848.
  • Shoji M, Iwakami N, Takeuchi S, et al . JNK activation is associated with intracellular beta-amyloid accumulation. Brain Res Mol Brain Res. 2000;85(1–2):221–233.
  • Vogel J, Anand VS, Ludwig B, et al. The JNK pathway amplifies and drives subcellular changes in tau phosphorylation. Neuropharmacology. [Internet]. 2009;57(56):539–550. http://dx.doi.org/10.1016/j.neuropharm.2009.07.021
  • Manning AM, Davis RJ. Targeting JNK for therapeutic benefit: from junk to gold? Nat Rev Drug Discov. 2003;2(7):554–565.
  • Troy CM, Rabacchi SA, Friedman WJ, et al. Caspase-2 mediates neuronal cell death induced by β-amyloid. J Neurosci. 2000;20(4):1386–1392.
  • She QB, Ma WY, Dong Z. Role of MAP kinases in UVB-induced phosphorylation of p53 at serine 20. Oncogene. 2002;21(10):1580–1589.
  • Levitan D, Lee J, Song L, et al. PS1 N- and C-terminal fragments form a complex that functions in APP processing and notch signaling. Proc Natl Acad Sci U S A. 2001;98(21):12186–12190.
  • Del Prete D, Checler F, Chami M. Ryanodine receptors: physiological function and deregulation in alzheimer disease. Mol Neurodegener. 2014; 9:21. https://pubmed.ncbi.nlm.nih.gov/24902695
  • Chan SL, Mayne M, Holden CP, et al. Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J Biol Chem. 2000;275(24):18195–18200.
  • Nakagawa T, Zhu H, Morishima N, et al . Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid- β . Nature. 2000;403(6765):98–103.
  • Yoneda T, Imaizumi K, Oono K, et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem. 2001;276(17):13935–13940.
  • Nijholt DAT, Van Haastert ES, Rozemuller AJM, et al. The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J Pathol. 2012;226(5):693–702.
  • Prasanthi JRP, Larson T, Schommer J, et al. Silencing gadd153/chop gene expression protects against Alzheimer’s disease-like pathology induced by 27-hydroxycholesterol in rabbit hippocampus. PLoS One. 2011;6(10):e26420.
  • Jope RS, Johnson GVW. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci. 2004;29(2):95–102.
  • Kim AJ, Shi Y, Austin RC, et al . Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3 . J Cell Sci. 2005;118(1):89–99.
  • Song L, De Sarno P, Jope RS . Central role of glycogen synthase kinase-3 β in endoplasmic reticulum stress-induced caspase-3 activation . J Biol Chem. 2002;277(47):44701–44708.
  • Ishizawa T, Sahara N, Ishiguro K, et al. Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice. Am J Pathol. 2003;163(3):1057–1067. http://dx.doi.org/10.1016/S0002-9440(10)63465-7
  • Gregersen N. Protein misfolding disorders: pathogenesis and intervention. J Inherit Metab Dis. 2006;29(2-3):456–470.
  • Rinnerthaler M, Richter K. The basics of biogerontology. In: Gerontology. Chapter 7; 2018.
  • Koren J, Jinwal UK, Lee DC, et al . Chaperone signalling complexes in Alzheimer’s disease. J Cell Mol Med. 2009;13(4):619–630.
  • Turturici G, Sconzo G, Geraci F. Hsp70 and its molecular role in nervous system diseases. Biochem Res Int. 2011;2011:618127.
  • Witte ME, Bol JGJM, Gerritsen WH, et al . Parkinson’s disease-associated parkin colocalizes with Alzheimer’s disease and multiple sclerosis brain lesions . Neurobiol Dis. 2009;36(3):445–452.
  • Hoshino T, Nakaya T, Araki W, et al . Endoplasmic reticulum chaperones inhibit the production of amyloid- β peptides. Biochem J. 2007;402(3):581–589.
  • Huttunen HJ, Guénette SY, Peach C, et al . HtrA2 regulates β -amyloid precursor protein (APP) metabolism through endoplasmic reticulum-associated degradation . J Biol Chem. 2007;282(38):28285–28295.
  • Kumar P, Ambasta RK, Veereshwarayya V, et al. CHIP and HSPs interact with β-APP in a proteasome-dependent manner and influence Aβ metabolism . Hum Mol Genet. 2007;16(7):848–864.
  • Wilhelmus MMM, Otte-Höller I, Wesseling P, et al . Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer’s disease brains. Neuropathol Appl Neurobiol. 2006;32(2):119–130.
  • Ansar S, Burlison JA, Hadden MK, et al . A non-toxic Hsp90 inhibitor protects neurons from Aβ-induced toxicity. Bioorg Med Chem Lett. 2007;17(7):1984–1990.
  • Dickey CA, Burrows F, Petrucelli L, et al. The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest. 2007;117(3):648–658.
  • Magrané J, Smith RC, Walsh K, et al. Heat shock protein 70 participates in the neuroprotective response to intracellularly expressed β-Amyloid in neurons. J Neurosci. 2004;24(7):1700–1706.
  • Calderwood SK, Murshid A. Molecular chaperone accumulation in cancer and decrease in Alzheimer’s disease: the potential roles of HSF1. Front Neurosci. 2017;11(APR):1–8.
  • Evans CG, Wisén S, Gestwicki JE . Heat shock proteins 70 and 90 inhibit early stages of amyloid β-(1-42) aggregation in vitro. J Biol Chem. 2006;281(44):33182–33191.
  • Dou F, Netzer WJ, Tanemura K, et al. Chaperones increase association of tau protein with microtubules. Proc Natl Acad Sci U S A. 2003;100(2):721–726.
  • Petrucelli L, Dickson D, Kehoe K, et al. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum Mol Genet. 2004;13(7):703–714.
  • Dabir DV, Trojanowski JQ, Richter-Landsberg C, et al. Expression of the small heat-shock protein αb-crystallin in tauopathies with glial pathology. Am J Pathol. 2004;164(1):155–166.
  • Björkdahl C, Sjögren MJ, Zhou X, et al . Small heat shock proteins Hsp27 or αB-crystallin and the protein components of neurofibrillary tangles: tau and neurofilaments . J Neurosci Res. 2008;86(6):1343–1352.
  • Unterberger U, Höftberger R, Gelpi E, et al. Endoplasmic reticulum stress features are prominent in alzheimer disease but not in prion diseases in vivo. J Neuropathol Exp Neurol. 2006;65(4):348–357.
  • Plácido AI, Pereira CMF, Duarte AI, et al . The role of endoplasmic reticulum in amyloid precursor protein processing and trafficking: implications for Alzheimer’s disease. Biochim Biophys Acta. 2014;1842(9):1444–1453.
  • Zhao J-H, Liu H-L, Lin H-Y, et al. Chemical chaperone and inhibitor discovery: potential treatments for protein conformational diseases. Perspect Medicin Chem. 2007;1:PMC.S212.
  • Papp E, Csermely P. Chemical chaperones: mechanisms of action and potential use. Mol Chaperones Heal Dis. 2005;(172):405–416.
  • Findeis M. Peptide inhibitors of beta amyloid aggregation. Curr Top Med Chem. 2002;2(4):417–423.
  • Yang DS, Yip CM, Huang THJ, et al . Manipulating the amyloid-beta aggregation pathway with chemical chaperones . J Biol Chem. 1999;274(46):32970–32974.
  • Liu R, Barkhordarian H, Emadi S, et al. Trehalose differentially inhibits aggregation and neurotoxicity of beta-amyloid 40 and 42. Neurobiol Dis. 2005;20(1):74–81.
  • Ueda T, Nagata M, Monji A, et al . Effect of sucrose on formation of the beta-amyloid fibrils and D-aspartic acids in Abeta 1-42 . Biol Pharm Bull. 2002;25(3):375–378.
  • Mimori S, Ohtaka H, Koshikawa Y, et al. 4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor. Bioorg Med Chem Lett. 2013;23(21):6015–6018.
  • Ricobaraza A, Cuadrado-Tejedor M, Pérez-Mediavilla A, et al . Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer’s disease mouse model. Neuropsychopharmacology. 2009;34(7):1721–1732.
  • Wiley JC, Meabon JS, Frankowski H, et al. Phenylbutyric acid rescues endoplasmic reticulum stress-induced suppression of APP proteolysis and prevents apoptosis in neuronal cells. PLoS One. 2010;5(2):e9135.
  • Nunes AF, Amaral JD, Lo AC, et al. TUDCA, a bile acid, attenuates amyloid precursor protein processing and amyloid-β deposition in APP/PS1 mice. Mol Neurobiol. 2012;45(3):440–454.
  • Lo AC, Callaerts-Vegh Z, Nunes AF, et al. R. Tauroursodeoxycholic acid (TUDCA) supplementation prevents cognitive impairment and amyloid deposition in APP/PS1 mice. Neurobiol Dis. 2013;50(1):21–29.
  • Kusaczuk M. Tauroursodeoxycholate—bile acid with chaperoning activity: molecular and cellular effects and therapeutic perspectives. Cells. 2019;8(12):1471.
  • Mecozzi VJ, Berman DE, Simoes S, et al. Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol. 2014;10(6):443–449.
  • Li JG, Chiu J, Ramanjulu M, et al. A pharmacological chaperone improves memory by reducing Aβ and tau neuropathology in a mouse model with plaques and tangles. Mol Neurodegener. 2020;15(1):1–11.
  • Ma Y, Yang M, Li X, et al. Therapeutic effects of natural drugs on Alzheimer’s Disease. Front Pharmacol. 2019;10:1355. https://doi.org/10.3389/fphar.2019.01355
  • Roy A. Role of medicinal plants against Alzheimer’s disease. Int J Complement Altern Med. 2018;11(4):205–208.
  • Chang K-H, Chen I-C, Lin H-Y, et al. The aqueous extract of Glycyrrhiza inflata can upregulate unfolded protein response-mediated chaperones to reduce tau misfolding in cell models of Alzheimer’s disease. Drug Des Devel Ther. 2016;10:885–896.
  • Chin D, Huebbe P, Pallauf K, et al. Neuroprotective properties of curcumin in Alzheimer’s disease – merits and limitations. Curr Med Chem. 2013;20(32):3955–85.
  • Luo Y, Smith JV, Paramasivam V, et al. Inhibition of amyloid-beta aggregation and caspase-3 activation by the ginkgo biloba extract EGb761. Proc Natl Acad Sci USA. 2002;99(19):12197–12202.
  • Arakawa T, Ejima D, Kita Y, et al. Small molecule pharmacological chaperones: from thermodynamic stabilization to pharmaceutical drugs. Biochim Biophys Acta. 2006;1764(11):1677–1687.
  • Cortez L, Sim V. The therapeutic potential of chemical chaperones in protein folding diseases. Prion. 2014;8(2):197–202.
  • Sampson HM, Robert R, Liao J, et al. Identification of a NBD1-binding pharmacological chaperone that corrects the trafficking defect of F508del-CFTR. Chem Biol. 2011;18(2):231–242.
  • Makley LN, McMenimen KA, DeVree BT, et al. Pharmacological chaperone for α-crystallin partially restores transparency in cataract models. Science. 2015;350(6261):674–677.
  • Borzova VA, Markossian KA, Kara DA, et al. Quantification of anti-aggregation activity of chaperones: a test-system based on dithiothreitol-induced aggregation of bovine serum albumin. PLoS One. 2013;8(9):e74367–18.
  • Conn PM, Smith E, Hodder P, et al. High-throughput screen for pharmacoperones of the vasopressin type 2 receptor. J Biomol Screen. 2013;18(8):930–937.
  • Alagramam KN, Gopal SR, Geng R, et al. A small molecule mitigates hearing loss in a mouse model of usher syndrome III. Nat Chem Biol. 2016;12(6):444–451.
  • Shin MH, Lim H-S. Screening methods for identifying pharmacological chaperones. Mol Biosyst. 2017;13(4):638–647. http://dx.doi.org/10.1039/C6MB00866F
  • Razavi H, Palaninathan SK, Powers ET, et al. Benzoxazoles as transthyretin amyloid fibril inhibitors: synthesis, evaluation, and mechanism of action. Angew Chem Int Ed Engl. 2003;42(24):2758–2761.
  • Cotrina EY, Gimeno A, Llop J, et al. An assay for screening potential drug candidates for Alzheimer’s disease that act as chaperones of the transthyretin and amyloid-β peptides interaction . Chemistry. 2020;26(72):17462–17469.
  • Kitakaze K, Taniuchi S, Kawano E, et al. Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity. eLife. 2019;8:1–26.
  • Sablón-Carrazana M, Fernández I, Bencomo A, et al. Drug development in conformational diseases: a novel family of chemical chaperones that bind and stabilise several polymorphic amyloid structures. PLoS ONE. 2015;10(9):e0135292–24.
  • Mimori S, Okuma Y, Kaneko M, et al. Discovery of synthetic methoxy-substituted 4-phenylbutyric acid derivatives as chemical chaperones. Chem Lett. 2013;42(9):1051–1052.
  • Mimori S, Koshikawa Y, Mashima Y, et al. Evaluation of synthetic naphthalene derivatives as novel chemical chaperones that mimic 4-phenylbutyric acid. Bioorg Med Chem Lett. 2015;25(4):811–814.
  • Mimori S, Okuma Y, Kaneko M, et al. Protective effects of 4-phenylbutyrate derivatives on the neuronal cell death and endoplasmic reticulum stress. Biol Pharm Bull. 2012;35(1):84–90.
  • Mimori S, Kawada K, Saito R, et al. Indole-3-propionic acid has chemical chaperone activity and suppresses endoplasmic reticulum stress-induced neuronal cell death. Biochem Biophys Res Commun. [Internet]. 2019;517(4):623–628. https://www.sciencedirect.com/science/article/pii/S0006291X19314287
  • Lin C-H, Wu Y-R, Kung P-J, et al. The potential of indole and a synthetic derivative for polyQ aggregation reduction by enhancement of the chaperone and autophagy systems. ACS Chem Neurosci. 2014;5(10):1063–1074.
  • Ozadali-Sari K, Tüylü Küçükkılınç T, Ayazgok B, et al . Novel multi-targeted agents for Alzheimer’s disease: synthesis, biological evaluation, and molecular modeling of novel 2-[4-(4-substituted piperazin-1-yl)phenyl]benzimidazoles . Bioorg Chem. 2017;72:208–214.
  • Guzior N, Wieckowska A, Panek D, et al . Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer’s disease. Curr Med Chem. 2015;22(3):373–404. https://pubmed.ncbi.nlm.nih.gov/25386820
  • Mondal S, Vashi Y, Ghosh P, et al. Amyloid targeting "Artificial Chaperone" impairs oligomer mediated neuronal damage and mitochondrial dysfunction associated with Alzheimer’s disease. ACS Chem Neurosci. 2020;11(20):3277–3287.
  • Lee Y-S, Lai D-M, Huang H-J, et al. Prebiotic lactulose ameliorates the cognitive deficit in Alzheimer’s disease mouse model through macroautophagy and chaperone-mediated autophagy pathways . J Agric Food Chem. 2021;69(8):2422–2437.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.