The unfolded protein response is activated in the olfactory system in Alzheimer\u2019s disease

Helen C Murray,Richard L M Faull,Birger Victor Dieriks,Praju Vikas Anekal,Maurice A Curtis,Alan Koretsky,Leonardo Belluscio,Molly E V Swanson,Clinton Turner

doi:10.1186/s40478-020-00986-7

Abstract

Olfactory dysfunction is an early and prevalent symptom of Alzheimer’s disease (AD) and the olfactory bulb is a nexus of beta-amyloid plaque and tau neurofibrillary tangle (NFT) pathology during early AD progression. To mitigate the accumulation of misfolded proteins, an endoplasmic reticulum stress response called the unfolded protein response (UPR) occurs in the AD hippocampus. However, chronic UPR activation can lead to apoptosis and the upregulation of beta-amyloid and tau production. Therefore, UPR activation in the olfactory system could be one of the first changes in AD. In this study, we investigated whether two proteins that signal UPR activation are expressed in the olfactory system of AD cases with low or high amounts of aggregate pathology. We used immunohistochemistry to label two markers of UPR activation (p-PERK and p-eIF2α) concomitantly with neuronal markers (NeuN and PGP9.5) and pathology markers (beta-amyloid and tau) in the olfactory bulb, piriform cortex, entorhinal cortex and the CA1 region of the hippocampus in AD and normal cases. We show that UPR activation, as indicated by p-PERK and p-eIF2α expression, is significantly increased throughout the olfactory system in AD cases with low (Braak stage III-IV) and high-level (Braak stage V-VI) pathology. We further show that UPR activation occurs in the mitral cells and in the anterior olfactory nucleus of the olfactory bulb where tau and amyloid pathology is abundant. However, UPR activation is not present in neurons when they contain NFTs and only rarely occurs in neurons containing diffuse tau aggregates. We conclude that UPR activation is prevalent in all regions of the olfactory system and support previous findings suggesting that UPR activation likely precedes NFT formation. Our data indicate that chronic UPR activation in the olfactory system might contribute to the olfactory dysfunction that occurs early in the pathogenesis of AD.

Highlights

Olfactory dysfunction is an early and prevalent symptom of Alzheimer’s disease (AD) that can precede the diagnostic memory and cognitive symptoms by many years [4, 12]
Results p-Protein kinase RNA-like ER kinase (PERK) and p-eukaryotic translation initiator factor 2α (eIF2α) are located in areas of the olfactory bulb affected by tau and beta-amyloid aggregation in AD To study unfolded protein response (UPR) activation in the olfactory system of AD patients and normal individuals, we performed immunohistochemistry with phosphorylated PERK (p-PERK) and phosphorylated eIF2α (p-eIF2α) antibodies on postmortem human brain sections
To determine whether the Inositolrequiring enzyme 1α (IRE1α) branch of the UPR pathway was activated in the olfactory bulb we labelled for p-IRE1α

Summary

Introduction

Olfactory dysfunction is an early and prevalent symptom of Alzheimer’s disease (AD) that can precede the diagnostic memory and cognitive symptoms by many years [4, 12]. In response to an accumulation of misfolded proteins, the ER chaperone BiP/GRP78 is released from PERK and binds to these misfolded proteins. This leads to the dimerisation and autophosphorylation of PERK and subsequent phosphorylation of its downstream effector eukaryotic translation initiator factor 2α (eIF2α). Activated eIF2α inhibits protein synthesis to alleviate the accumulation of misfolded proteins, but increases translation of ATF4 which can drive apoptosis via C/EBP-homologous protein (CHOP). Prolonged activation of this proapoptotic pathway of the UPR leads to synaptic failure and neuronal loss [29]

Methods

Results

Conclusion