The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies

Abstract

The unfolded protein response (UPR) is a stress response activated upon disturbed homeostasis in the endoplasmic reticulum (ER). Previously, we reported that the activation of the UPR closely correlates with the presence of phosphorylated tau (p-tau) in Alzheimer's disease (AD). As well as increased presence of intracellular p-tau, AD brains are characterized by extracellular deposits of β amyloid (Aβ). Recent in vitro studies have shown that Aβ can induce ER stress and activation of the UPR. The aim of the present study is to investigate UPR activation in sporadic tauopathies like progressive supranuclear palsy (PSP) and Pick's disease (PiD), and familial cases with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) which carry mutations in the gene encoding for tau (MAPT). The presence of phosphorylated pancreatic ER kinase (pPERK) and phosphorylated inositol requiring enzyme 1α (pIRE1), which are indicative of an activated UPR, was assessed by immunohistochemistry in cases neuropathologically defined as frontotemporal lobar degeneration with tau pathology (FTLD-tau). Increased presence of UPR activation markers pPERK and pIRE1 was observed in neurons and glia in FTLD-tau cases, in contrast to FTLD subtypes negative for tau pathology or in non-neurological controls. pPERK and pIRE1 were also prominently present in relatively young carriers of MAPT mutation. A strong association between the presence of UPR activation markers and p-tau was observed in the hippocampus of FTLD-tau cases. Double immunohistochemical staining on FTLD-tau cases revealed that UPR activation is predominantly observed in neurons that show diffuse staining of p-tau. These data demonstrate that UPR activation is intimately connected with the accumulation and aggregation of p-tau, and occurs independently from Aβ deposits. Our findings provide new pathological insight into the close association between p-tau and UPR activation in tauopathies.

Melatonin suppresses methamphetamine-triggered endoplasmic reticulum stress in C6 cells glioma cell lines

“…Melatonin suppressed the upregulation of CHOP and caspase -12 induced by METH. Increased expression of CHOP triggers the ER stress-induced cell death that is mostly found in various neurodegenerative diseases such as ischemia and Alzheimer's disease (Lindholm et al, 2006;Doyle et al, 2011;Larner et al, 2006;Nijholt et al, 2012). This result suggested that melatonin improves ER function, thereby suppressing ER stress-induced cell death.…”

Regulation of mRNA Translation in Neurons—A Matter of Life and Death

“…Subsequently, increased levels of p-eIF2α were found in the cortex and hippocampus of AD patients and in AD mouse models (Chang et al, 2002b; Devi and Ohno, 2013; Hoozemans et al, 2009; Kim et al, 2007; Lewerenz and Maher, 2009; Ma et al, 2013; Mouton-Liger et al, 2012; O’Connor et al, 2008; Page et al, 2006; Stutzbach et al, 2013; Unterberger et al, 2006). In addition to AD, p-eIF2α levels are elevated in the brain or spinal cord of patients and mice with prion disease (Unterberger et al, 2006), amyotrophic lateral sclerosis (ALS; Ilieva et al, 2007), Parkinson’s disease (PD; Hoozemans et al, 2007, 2012), Huntington’s disease (HD; Leitman et al, 2014), and various tauopathies (Köhler et al, 2014; Nijholt et al, 2012; Radford et al, 2015; Stutzbach et al, 2013; Unterberger et al, 2006). …”

Allicin improves endoplasmic reticulum stress-related cognitive deficits via PERK/Nrf2 antioxidative signaling pathway

“…13 Accumulating evidences show that ER stress induces tau phosphorylation (Ho et al, 2012), as well, reduces amyloid β peptide secretion (Suga K et al, 2015) and finally causes Aβ accumulation (Liu et al, 2012). Conversely, abnormal tau phosphorylation and Aβ deposit activate ER stress and mitochondria apoptosis pathway to cause neuronal death in the neurodegenerative process (Costa et al, 2013;Ho et al, 2012;Nijholt et al, 2012;Pinkaew et al, 2015). This positive loop may play an important role in the development of AD.…”