Heat Shock Proteins in Alzheimer's Disease: Role and Targeting

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2018 Sep 12

PMID 30200516

Citations 74

Authors

Claudia Campanella

Andrea Pace

Celeste Caruso Bavisotto

Paola Marzullo

Antonella Marino Gammazza

Silvestre Buscemi

Antonio Palumbo Piccionello

Affiliations

Soon will be listed here.

Abstract

Among diseases whose cure is still far from being discovered, Alzheimer's disease (AD) has been recognized as a crucial medical and social problem. A major issue in AD research is represented by the complexity of involved biochemical pathways, including the nature of protein misfolding, which results in the production of toxic species. Considering the involvement of (mis)folding processes in AD aetiology, targeting molecular chaperones represents a promising therapeutic perspective. This review analyses the connection between AD and molecular chaperones, with particular attention toward the most important heat shock proteins (HSPs) as representative components of the human chaperome: Hsp60, Hsp70 and Hsp90. The role of these proteins in AD is highlighted from a biological point of view. Pharmacological targeting of such HSPs with inhibitors or regulators is also discussed.

Citing Articles

Hyperthermia and targeting heat shock proteins: innovative approaches for neurodegenerative disorders and Long COVID.

Smadja D, Abreu M Front Neurosci. 2025; 19:1475376.

PMID: 39967803 PMC: 11832498. DOI: 10.3389/fnins.2025.1475376.

Alzheimer's Disease and : Exploring the Links.

Shawkatova I, Durmanova V, Javor J Life (Basel). 2025; 15(1).

PMID: 39860036 PMC: 11766648. DOI: 10.3390/life15010096.

Stereo-seq of the prefrontal cortex in aging and Alzheimer's disease.

Gong Y, Haeri M, Zhang X, Li Y, Liu A, Wu D Nat Commun. 2025; 16(1):482.

PMID: 39779708 PMC: 11711495. DOI: 10.1038/s41467-024-54715-y.

Localized molecular chaperone synthesis maintains neuronal dendrite proteostasis.

Alecki C, Rizwan J, Le P, Jacob-Tomas S, Comaduran M, Verbrugghe M Nat Commun. 2024; 15(1):10796.

PMID: 39737952 PMC: 11685665. DOI: 10.1038/s41467-024-55055-7.

Spatial proteomic differences in chronic traumatic encephalopathy, Alzheimer's disease, and primary age-related tauopathy hippocampi.

Richardson T, Orr M, Orr T, Rohde S, Ehrenberg A, Thorn E Alzheimers Dement. 2024; 21(2):e14487.

PMID: 39737785 PMC: 11848160. DOI: 10.1002/alz.14487.

References

Chakravarty A, Jarosz D . More than Just a Phase: Prions at the Crossroads of Epigenetic Inheritance and Evolutionary Change. J Mol Biol. 2018; 430(23):4607-4618. PMC: 6204307. DOI: 10.1016/j.jmb.2018.07.017. View

Sun Y, Zhang J, Chen S . Suppression of Alzheimer's disease-related phenotypes by the heat shock protein 70 inducer, geranylgeranylacetone, in APP/PS1 transgenic mice via the ERK/p38 MAPK signaling pathway. Exp Ther Med. 2017; 14(6):5267-5274. PMC: 5740803. DOI: 10.3892/etm.2017.5253. View

Biamonte M, Van de Water R, Arndt J, Scannevin R, Perret D, Lee W . Heat shock protein 90: inhibitors in clinical trials. J Med Chem. 2010; 53(1):3-17. DOI: 10.1021/jm9004708. View

Yang X, Cai P, Liu Q, Wu J, Yin Y, Wang X . Novel 8-hydroxyquinoline derivatives targeting β-amyloid aggregation, metal chelation and oxidative stress against Alzheimer's disease. Bioorg Med Chem. 2018; 26(12):3191-3201. DOI: 10.1016/j.bmc.2018.04.043. View

Turturici G, Sconzo G, Geraci F . Hsp70 and its molecular role in nervous system diseases. Biochem Res Int. 2011; 2011:618127. PMC: 3049350. DOI: 10.1155/2011/618127. View

Campanella C, DAnneo A, Marino Gammazza A, Caruso Bavisotto C, Barone R, Emanuele S . The histone deacetylase inhibitor SAHA induces HSP60 nitration and its extracellular release by exosomal vesicles in human lung-derived carcinoma cells. Oncotarget. 2015; 7(20):28849-67. PMC: 5045361. DOI: 10.18632/oncotarget.6680. View

Lu Y, Ansar S, Michaelis M, Blagg B . Neuroprotective activity and evaluation of Hsp90 inhibitors in an immortalized neuronal cell line. Bioorg Med Chem. 2009; 17(4):1709-15. PMC: 2729088. DOI: 10.1016/j.bmc.2008.12.047. View

Martorana A, Giacalone V, Bonsignore R, Pace A, Gentile C, Pibiri I . Heterocyclic Scaffolds for the Treatment of Alzheimer's Disease. Curr Pharm Des. 2016; 22(26):3971-95. DOI: 10.2174/1381612822666160518141650. View

Gupta R, Ramachandra N, Bowes T, Singh B . Unusual cellular disposition of the mitochondrial molecular chaperones Hsp60, Hsp70 and Hsp10. Novartis Found Symp. 2008; 291:59-68. DOI: 10.1002/9780470754030.ch5. View

10.

Rousaki A, Miyata Y, Jinwal U, Dickey C, Gestwicki J, Zuiderweg E . Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones. J Mol Biol. 2011; 411(3):614-32. PMC: 3146629. DOI: 10.1016/j.jmb.2011.06.003. View

11.

Ansar S, Burlison J, Hadden M, Yu X, Desino K, Bean J . A non-toxic Hsp90 inhibitor protects neurons from Abeta-induced toxicity. Bioorg Med Chem Lett. 2007; 17(7):1984-90. DOI: 10.1016/j.bmcl.2007.01.017. View

12.

Chatterjee S, Burns T . Targeting Heat Shock Proteins in Cancer: A Promising Therapeutic Approach. Int J Mol Sci. 2017; 18(9). PMC: 5618627. DOI: 10.3390/ijms18091978. View

13.

Campanella C, Rappa F, Sciume C, Marino Gammazza A, Barone R, Bucchieri F . Heat shock protein 60 levels in tissue and circulating exosomes in human large bowel cancer before and after ablative surgery. Cancer. 2015; 121(18):3230-9. DOI: 10.1002/cncr.29499. View

14.

Inda C, Bolaender A, Wang T, Gandu S, Koren 3rd J . Stressing Out Hsp90 in Neurotoxic Proteinopathies. Curr Top Med Chem. 2016; 16(25):2829-38. PMC: 4995127. DOI: 10.2174/1568026616666160413141350. View

15.

Chen Q, Prior M, Dargusch R, Roberts A, Riek R, Eichmann C . A novel neurotrophic drug for cognitive enhancement and Alzheimer's disease. PLoS One. 2011; 6(12):e27865. PMC: 3237323. DOI: 10.1371/journal.pone.0027865. View

16.

Koren 3rd J, Jinwal U, Lee D, Jones J, Shults C, Johnson A . Chaperone signalling complexes in Alzheimer's disease. J Cell Mol Med. 2009; 13(4):619-30. PMC: 2749087. DOI: 10.1111/j.1582-4934.2008.00557.x. View

17.

Repalli J, Meruelo D . Screening strategies to identify HSP70 modulators to treat Alzheimer's disease. Drug Des Devel Ther. 2015; 9:321-31. PMC: 4294646. DOI: 10.2147/DDDT.S72165. View

18.

Terenzi A, Barone G, Palumbo Piccionello A, Giorgi G, Guarcello A, Portanova P . Synthesis, characterization, cellular uptake and interaction with native DNA of a bis(pyridyl)-1,2,4-oxadiazole copper(II) complex. Dalton Trans. 2010; 39(38):9140-5. DOI: 10.1039/c0dt00266f. View

19.

Alexopoulou Z, Lang J, Perrett R, Elschami M, Hurry M, Kim H . Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease. Proc Natl Acad Sci U S A. 2016; 113(32):E4688-97. PMC: 4987833. DOI: 10.1073/pnas.1523597113. View

20.

Ban H, Shimizu K, Minegishi H, Nakamura H . Identification of HSP60 as a primary target of o-carboranylphenoxyacetanilide, an HIF-1alpha inhibitor. J Am Chem Soc. 2010; 132(34):11870-1. DOI: 10.1021/ja104739t. View