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Targeting the Unfolded Protein Response as a Disease-Modifying Pathway in Dementia.

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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.



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Int J Mol Sci

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European Research Council (647479)
Wellcome Trust (via MRC) (201487/Z/16/Z)
UK Dementia Research Institute (DRICam17/18)
Medical Research Council (MR/R024820/1)
Goldman Sachs Gives (UK) (Unknown)
Medical Research Council (MR/S00503X/1)
National Institute for Health Research (NIHRDH-IS-BRC-1215-20014)
NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) (JOB). UK Dementia Research Institute (funded by the Medical Research Council UK, Alzheimer's Research UK and the Alzheimer's Society) (G.R.M., H.S.), the Cambridge Centre for Parkinson-Plus (G.R.M. and A.B.) the European Research Council (consolidator grant UPR Neuro; no. 647479), the Joint Proramme Neurodegenerative Disease, the Centres of Excellence in Neurodegeneration and the Well come Trust Collaborative Award (G.R.M). Gnodde Goldman Sachs Translational Neuroscience (B.U &E.S)