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

Abstract

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.

Keywords: Alzheimer’s disease; dementia; integrated stress response; neurocognitive disorders; neurodegenerative disorders; neuroprotection; trazodone; unfolded protein response.

Figure 1

Markers of UPR activation associated with pathological protein deposition in neurodegenerative disordersProteins associated with UPR activation are seen in association with protein aggregates in specific brain regions in patients with different neurodegenerative diseases. Inositol-requiring enzyme 1 (IRE1) and protein kinase RNA-like endoplasmic reticulum kinase (PERK) are key sensory proteins for ER stress, and are activated in frontotemporal dementia and Alzheimer’s disease. p-PERK and its downstream substrate eukaryotic initiation factor 2 (eIF2)—p-eIF2α—are also activated in Parkinson’s disease, Alzheimer’s disease, and progressive supranuclear palsy. For a review, see Hetz and Saxena (2017) [35].

Figure 2

Schematic showing points of action of drugs and experimental compounds targeting the PERK branch of the UPR and ISR. (1) The chaperone protein known as binding immunoglobulin protein (BiP) binds to misfolded proteins, resulting in (2) phosphorylation of PERK. PERK activation, in turn, leads to (3) phosphorylation of eIF2α, which reduces protein translation (4) via by preventing nucleotide exchange by eIF2B needed for initiation of translation. GSK260414 inhibits PERK phosphorylation; ISRIB prevents eIF2B binding by p-eIF2α, and trazodone also acts downstream of p-eIF2α by restoring global protein synthesis rates. Intervention at all of these steps provides exceptional neuroprotection in many animal models of neurodegenerative diseases.