3-(3-oxoisoindolin-1-yl)pentane-2, 4-dione (ISOAC1) as a new molecule able to inhibit Amyloid ß aggregation and neurotoxicity (230 views)
Biomedicine & Pharmacotherapy, 2023 Oct; 168: 115745-115745.
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Paper type: Research Journal Article
Impact factor: 7.5, 5-year impact factor: 0
Url: https://doi.org/10.1016/j.biopha.2023.115745
Keywords: β-Diketone-3-Substituted Isoindolinone Amyloid β 1–42 Aggregation Alzheimer’s Disease Neuroprotection
Affiliations:
*** IBB - CNR ***
aDivision of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Naples, ItalybDepartment of Pharmacy, Federico II University of Naples, Naples, ItalycInstitute of Biostructures and Bioimaging, Italian National CouncdDepartment of Chemistry and Biology “A. Zambelli”, University of Salerno, Fisciano, SA, ItalyeDepartment of Molecular Medicine and Medical Biotechnologies, Federico II University of Naples, Naples, ItalyfDepartment of Pharmacy, University of Salerno, Fisciano, SA, Italy
References:
H.W. Querfurth, F.M. LaFerla
Alzheimer's disease
N. Engl. J. Med, 362 (2010), pp. 329-344, 10.1056/NEJMra0909142
","iconSize":"small","show":true}],"integratorId":8301}" doc-id="10.1056/NEJMra0909142" doc-type="doi" tooltip-placement="left" style="display: inline-block; position: relative; box-sizing: border-box; margin: 0px; padding: 0px;"> View article
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Physiol. Rev., 81 (2001), pp. 741-766, 10.1152/physrev.2001.81.2.741
J.C. Morris, M. Storandt, D.W. McKeel Jr, E.H. Rubin, J.L. Price, E.A. Grant, L. Berg
Cerebral amyloid deposition and diffuse plaques in "normal" aging: evidence for presymptomatic and very mild Alzheimer's disease
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G.B. Irvine, O.M. El-Agnaf, G.M. Shankar, D.M. Walsh
Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases
Mol. Med., 14 (2008), pp. 451-464, 10.2119/2007-00100.Irvine
A. Lorenzo, B.A. Yankner
Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red
Proc. Natl. Acad. Sci. U. S. A., 91 (1994), pp. 12243-12247, 10.1073/pnas.91.25.12243
K. Ueda, S. Shinohara, T. Yagami, K. Asakura, K. Kawasaki
Amyloid beta protein potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels: a possible involvement of free radicals
J. Neurochem., 68 (1997), pp. 265-271, 10.1046/j.1471-4159.1997.68010265.x
M. Shoji, T.E. Golde, J. Ghiso, T.T. Cheung, S. Estus, L.M. Shaffer, X.D. Cai, D.M. McKay, R. Tintner, B. Frangione, et al.
Production of the Alzheimer amyloid beta protein by normal proteolytic processing
Science, 258 (1992), pp. 126-129, 10.1126/science.1439760
C. Priller, T. Bauer, G. Mitteregger, B. Krebs, H.A. Kretzschmar, J. Herms
Synapse formation and function is modulated by the amyloid precursor protein
J. Neurosci., 26 (2006), pp. 7212-7221, 10.1523/JNEUROSCI.1450-06.2006
R. Pellarin, A. Caflisch
Interpreting the aggregation kinetics of amyloid peptides
J. Mol. Biol., 360 (2006), pp. 882-892, 10.1016/j.jmb.2006.05.033
View PDFView articleView in ScopusGoogle Scholar
M.P. Lambert, K.L. Viola, B.A. Chromy, L. Chang, T.E. Morgan, J. Yu, D.L. Venton, G.A. Krafft, C.E. Finch, W.L. Klein
Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies
J. Neurochem., 79 (2001), pp. 595-605, 10.1046/j.1471-4159.2001.00592.x
Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior
Behav. Brain Res., 192 (2008), pp. 106-113, 10.1016/j.bbr.2008.02.016
K. Broersen, F. Rousseau, J. Schymkowitz
The culprit behind amyloid beta peptide related neurotoxicity in Alzheimer's disease: oligomer size or conformation?
Alzheimers Res. Ther., 2 (2010), p. 12, 10.1186/alzrt36
Translating cell biology into therapeutic advances in Alzheimer's disease
Nature, 399 (1999), pp. A23-A31, 10.1038/399a023
A. Miranda, E. Montiel, H. Ulrich, C. Paz
Selective secretase targeting for Alzheimer's disease therapy
J. Alzheimers Dis., 81 (2021), pp. 1-17, 10.3233/JAD-201027
S.H. Barage, K.D. Sonawane
Amyloid cascade hypothesis: pathogenesis and therapeutic strategies in Alzheimer's disease
Neuropeptides, 52 (2015), pp. 1-18, 10.1016/j.npep.2015.06.008
A. Gea-González, S. Hernández-García, P. Henarejos-Escudero, P. Martínez-Rodríguez, F. García-Carmona, F. Gandía-Herrero
Polyphenols from traditional Chinese medicine and Mediterranean diet are effective against Aβ toxicity in vitro and in vivo in Caenorhabditis elegans
Food Funct., 13 (2022), pp. 1206-1217, 10.1039/d1fo02147h
Biomedicine & Pharmacotherapy, 2023 Oct; 168: 115745-115745.
Export to BibTeX Export to EndNote
Paper type: Research Journal Article
Impact factor: 7.5, 5-year impact factor: 0
Url: https://doi.org/10.1016/j.biopha.2023.115745
Keywords: β-Diketone-3-Substituted Isoindolinone Amyloid β 1–42 Aggregation Alzheimer’s Disease Neuroprotection
Affiliations:
*** IBB - CNR ***
aDivision of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, Federico II University of Naples, Naples, ItalybDepartment of Pharmacy, Federico II University of Naples, Naples, ItalycInstitute of Biostructures and Bioimaging, Italian National CouncdDepartment of Chemistry and Biology “A. Zambelli”, University of Salerno, Fisciano, SA, ItalyeDepartment of Molecular Medicine and Medical Biotechnologies, Federico II University of Naples, Naples, ItalyfDepartment of Pharmacy, University of Salerno, Fisciano, SA, Italy
References:
H.W. Querfurth, F.M. LaFerla
Alzheimer's disease
N. Engl. J. Med, 362 (2010), pp. 329-344, 10.1056/NEJMra0909142
","iconSize":"small","show":true}],"integratorId":8301}" doc-id="10.1056/NEJMra0909142" doc-type="doi" tooltip-placement="left" style="display: inline-block; position: relative; box-sizing: border-box; margin: 0px; padding: 0px;"> View article
View in ScopusGoogle Scholar
Physiol. Rev., 81 (2001), pp. 741-766, 10.1152/physrev.2001.81.2.741
J.C. Morris, M. Storandt, D.W. McKeel Jr, E.H. Rubin, J.L. Price, E.A. Grant, L. Berg
Cerebral amyloid deposition and diffuse plaques in "normal" aging: evidence for presymptomatic and very mild Alzheimer's disease
Neurology, 46 (1996), pp. 707-719, 10.1212/wnl.46.3.707
G.B. Irvine, O.M. El-Agnaf, G.M. Shankar, D.M. Walsh
Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases
Mol. Med., 14 (2008), pp. 451-464, 10.2119/2007-00100.Irvine
A. Lorenzo, B.A. Yankner
Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red
Proc. Natl. Acad. Sci. U. S. A., 91 (1994), pp. 12243-12247, 10.1073/pnas.91.25.12243
K. Ueda, S. Shinohara, T. Yagami, K. Asakura, K. Kawasaki
Amyloid beta protein potentiates Ca2+ influx through L-type voltage-sensitive Ca2+ channels: a possible involvement of free radicals
J. Neurochem., 68 (1997), pp. 265-271, 10.1046/j.1471-4159.1997.68010265.x
M. Shoji, T.E. Golde, J. Ghiso, T.T. Cheung, S. Estus, L.M. Shaffer, X.D. Cai, D.M. McKay, R. Tintner, B. Frangione, et al.
Production of the Alzheimer amyloid beta protein by normal proteolytic processing
Science, 258 (1992), pp. 126-129, 10.1126/science.1439760
C. Priller, T. Bauer, G. Mitteregger, B. Krebs, H.A. Kretzschmar, J. Herms
Synapse formation and function is modulated by the amyloid precursor protein
J. Neurosci., 26 (2006), pp. 7212-7221, 10.1523/JNEUROSCI.1450-06.2006
R. Pellarin, A. Caflisch
Interpreting the aggregation kinetics of amyloid peptides
J. Mol. Biol., 360 (2006), pp. 882-892, 10.1016/j.jmb.2006.05.033
View PDFView articleView in ScopusGoogle Scholar
M.P. Lambert, K.L. Viola, B.A. Chromy, L. Chang, T.E. Morgan, J. Yu, D.L. Venton, G.A. Krafft, C.E. Finch, W.L. Klein
Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies
J. Neurochem., 79 (2001), pp. 595-605, 10.1046/j.1471-4159.2001.00592.x
Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior
Behav. Brain Res., 192 (2008), pp. 106-113, 10.1016/j.bbr.2008.02.016
K. Broersen, F. Rousseau, J. Schymkowitz
The culprit behind amyloid beta peptide related neurotoxicity in Alzheimer's disease: oligomer size or conformation?
Alzheimers Res. Ther., 2 (2010), p. 12, 10.1186/alzrt36
Translating cell biology into therapeutic advances in Alzheimer's disease
Nature, 399 (1999), pp. A23-A31, 10.1038/399a023
A. Miranda, E. Montiel, H. Ulrich, C. Paz
Selective secretase targeting for Alzheimer's disease therapy
J. Alzheimers Dis., 81 (2021), pp. 1-17, 10.3233/JAD-201027
S.H. Barage, K.D. Sonawane
Amyloid cascade hypothesis: pathogenesis and therapeutic strategies in Alzheimer's disease
Neuropeptides, 52 (2015), pp. 1-18, 10.1016/j.npep.2015.06.008
A. Gea-González, S. Hernández-García, P. Henarejos-Escudero, P. Martínez-Rodríguez, F. García-Carmona, F. Gandía-Herrero
Polyphenols from traditional Chinese medicine and Mediterranean diet are effective against Aβ toxicity in vitro and in vivo in Caenorhabditis elegans
Food Funct., 13 (2022), pp. 1206-1217, 10.1039/d1fo02147h
3-(3-oxoisoindolin-1-yl)pentane-2, 4-dione (ISOAC1) as a new molecule able to inhibit Amyloid ß aggregation and neurotoxicity
Amyloid β 1–42 (Aβ1–42) protein aggregation is considered one of the main triggers of Alzheimer’s disease (AD). In this study, we examined the in vitro anti-amyloidogenic activity of the isoindolinone derivative 3-(3-oxoisoindolin-1-yl)pentane-2,4-dione (ISOAC1) and its neuroprotective potential against the Aβ1–42 toxicity. By performing the Thioflavin T fluorescence assay, Western blotting analyses, and Circular Dichroism experiments, we found that ISOAC1 was able to reduce the Aβ1–42 aggregation and conformational transition towards β-sheet structures. Interestingly, in silico studies revealed that ISOAC1 was able to bind to both the monomer and a pentameric protofibril of Aβ1–42, establishing a hydrophobic interaction with the PHE19 residue of the Aβ1–42 KLVFF motif. In vitro analyses on primary cortical neurons showed that ISOAC1 counteracted the increase of intracellular Ca2+ levels and decreased the Aβ1–42-induced toxicity, in terms of mitochondrial activity reduction and increase of reactive oxygen species production. In addition, confocal microscopy analyses showed that ISOAC1 was able to reduce the Aβ1–42 intraneuronal accumulation. Collectively, our results clearly show that ISOAC1 exerts a neuroprotective effect by reducing the Aβ1–42 aggregation and toxicity, hence emerging as a promising compound for the development of new Aβ-targeting therapeutic strategies for AD treatment.
Amyloid β 1–42 (Aβ1–42) protein aggregation is considered one of the main triggers of Alzheimer’s disease (AD). In this study, we examined the in vitro anti-amyloidogenic activity of the isoindolinone derivative 3-(3-oxoisoindolin-1-yl)pentane-2,4-dione (ISOAC1) and its neuroprotective potential against the Aβ1–42 toxicity. By performing the Thioflavin T fluorescence assay, Western blotting analyses, and Circular Dichroism experiments, we found that ISOAC1 was able to reduce the Aβ1–42 aggregation and conformational transition towards β-sheet structures. Interestingly, in silico studies revealed that ISOAC1 was able to bind to both the monomer and a pentameric protofibril of Aβ1–42, establishing a hydrophobic interaction with the PHE19 residue of the Aβ1–42 KLVFF motif. In vitro analyses on primary cortical neurons showed that ISOAC1 counteracted the increase of intracellular Ca2+ levels and decreased the Aβ1–42-induced toxicity, in terms of mitochondrial activity reduction and increase of reactive oxygen species production. In addition, confocal microscopy analyses showed that ISOAC1 was able to reduce the Aβ1–42 intraneuronal accumulation. Collectively, our results clearly show that ISOAC1 exerts a neuroprotective effect by reducing the Aβ1–42 aggregation and toxicity, hence emerging as a promising compound for the development of new Aβ-targeting therapeutic strategies for AD treatment.
3-(3-oxoisoindolin-1-yl)pentane-2, 4-dione (ISOAC1) as a new molecule able to inhibit Amyloid ß aggregation and neurotoxicity
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