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dc.contributor.authorSidhom, Emad
dc.contributor.authorO’Brien, John T
dc.contributor.authorButcher, Adrian
dc.contributor.authorSmith, Heather
dc.contributor.authorMallucci, Giovanna
dc.contributor.authorUnderwood, Benjamin
dc.date.accessioned2022-02-14T02:01:57Z
dc.date.available2022-02-14T02:01:57Z
dc.date.issued2022-02-11
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/333978
dc.description.abstract<jats:p>Dementia is a global medical and societal challenge; it has devastating personal, social and economic costs, which will increase rapidly as the world’s population ages. Despite this, there are no disease-modifying treatments for dementia; current therapy modestly improves symptoms but does not change the outcome. Therefore, new treatments are urgently needed—particularly any that can slow down the disease’s progression. Many of the neurodegenerative diseases that lead to dementia are characterised by common pathological responses to abnormal protein production and misfolding in brain cells, raising the possibility of the broad application of therapeutics that target these common processes. The unfolded protein response (UPR) is one such mechanism. The UPR is a highly conserved cellular stress response to abnormal protein folding and is widely dysregulated in neurodegenerative diseases. In this review, we describe the basic machinery of the UPR, as well as the evidence for its overactivation and pathogenicity in dementia, and for the marked neuroprotective effects of its therapeutic manipulation in murine models of these disorders. We discuss drugs identified as potential UPR-modifying therapeutic agents—in particular the licensed antidepressant trazodone—and we review epidemiological and trial data from their use in human populations. Finally, we explore future directions for investigating the potential benefit of using trazodone or similar UPR-modulating compounds for disease modification in patients with dementia.</jats:p>
dc.languageen
dc.publisherMDPI AG
dc.subjectdementia
dc.subjectAlzheimer’s disease
dc.subjecttrazodone
dc.subjectunfolded protein response
dc.subjectintegrated stress response
dc.subjectneuroprotection
dc.subjectneurodegenerative disorders
dc.subjectneurocognitive disorders
dc.titleTargeting the Unfolded Protein Response as a Disease-Modifying Pathway in Dementia
dc.typeArticle
dc.date.updated2022-02-14T02:01:56Z
prism.issueIdentifier4
prism.publicationNameInternational Journal of Molecular Sciences
prism.volume23
dc.identifier.doi10.17863/CAM.81395
dcterms.dateAccepted2022-01-26
rioxxterms.versionofrecord10.3390/ijms23042021
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidSidhom, Emad [0000-0003-1733-8211]
dc.contributor.orcidButcher, Adrian [0000-0001-5723-8720]
dc.contributor.orcidMallucci, Giovanna [0000-0001-8504-1191]
dc.contributor.orcidUnderwood, Benjamin [0000-0003-3427-9487]
dc.identifier.eissn1422-0067
cam.issuedOnline2022-02-11


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