Key role of MIF-related neuroinflammation in neurodegeneration and cognitive impairment in Alzheimer\u2019s disease

Elham Nasiri,Michael Bacher,Henriette Dietrich,Patricio T Huerta,Julius Popp,Roman Sankowski,Aikaterini Oikonomidi,Yousef Al-Abed

doi:10.1186/s10020-020-00163-5

Abstract

BackgroundMacrophage Migration Inhibitory Factor (MIF) is a potent proinflammatory cytokine that promotes the production of other immune mediators. MIF is produced by most cell types in the brain including microglia, astrocytes and neurons. Enhanced expression of MIF might contribute to the persistent activation of glial, chronic neuroinflammation and neurodegeneration. Here, we investigated the effect of MIF on inflammatory markers and spatial learning in a mouse model of sporadic AD and on tau pathology in AD patients.MethodsWe examined the effects of MIF deficiency and pharmacological MIF inhibition in vitro and in vivo. In vitro, quantitative PCR and ELISA were used to assess cytokine production of STZ-treated glial cells. In vivo, C57BL/6 mice were subjected to intracerebroventricular streptozotocin injection (3 mg/kg, ICV-STZ). Neuroinflammation and contextual learning performance were assessed using quantitative PCR and fear conditioning, respectively. Pharmacological MIF inhibition was achieved with intraperitoneal injections of ISO-1 (daily, IP, 20 mg/kg in 5% DMSO in 0.9% NaCl) for 4 weeks following ICV-STZ injection. The findings from ISO-1 treated mice were confirmed in MIF knockout C57BL/6. To assess the role of MIF in human AD, cerebrospinal fluid levels of MIF and hyperphosphorylated tau were measured using ELISA.ResultsAdministration ICV-STZ resulted in hippocampal dependent cognitive impairment. MIF inhibition with ISO-1 significantly improved the STZ-induced impairment in contextual memory performance, indicating MIF-related inflammation as a major contributor to ICV-STZ-induced memory deficits. Furthermore, inhibition of the MIF resulted in reduced cytokine production in vitro and in vivo.In human subjects with AD at early clinical stages, cerebrospinal fluid levels of MIF were increased in comparison with age-matched controls, and correlated with biomarkers of tau hyper-phosphorylation and neuronal injury hinting at MIF levels as a potential biomarker for early-stage AD.ConclusionsThe present study indicates the key role of MIF in controlling the chronic cytokine release in neuroinflammation related to tau hyperphosphorylation, neurodegeneration, and clinical manifestations of AD, suggesting the potential of MIF inhibition as therapeutic strategy to slow down neurodegeneration and clinical disease progression.

Highlights

The present study indicates the key role of Migration Inhibitory Factor (MIF) in controlling the chronic cytokine release in neuroinflammation related to tau hyperphosphorylation, neurodegeneration, and clinical manifestations of Alzheimer’s Disease (AD), suggesting the potential of MIF inhibition as therapeutic strategy to slow down neurodegeneration and clinical disease progression
Alzheimer’s Disease (AD) is an aging-associated disease defined by progressive neurodegeneration, neuroinflammation and the presence of protein aggregates consisting of amyloid β (Aβ) and hyperphosphorylated tau (Selkoe 2001)
A rationale for implicating inflammatory diseases in AD etiology has been provided by genomic studies showing associations between AD and polymorphisms in a number of genes involved in immune cell function, such as Apolipoprotein E (APOE), Triggering receptor expressed on myeloid cells 2 (TREM2), CD33 (Jonsson et al 2013; Guerreiro et al 2013; Griciuc et al 2013)

Summary

Introduction

Alzheimer’s Disease (AD) is an aging-associated disease defined by progressive neurodegeneration, neuroinflammation and the presence of protein aggregates consisting of amyloid β (Aβ) and hyperphosphorylated tau (Selkoe 2001). While Aβ-centric therapies have largely failed to show clinical efficacy, several immunomodulatory therapeutic approaches have been investigated to target chronic neuroinflammation as a key component of AD pathogenesis (Varvel et al 2009; Lim et al 2000; Yan et al 2003). Epidemiological evidence and studies in different mouse models have suggested that blocking chronic inflammation associated with the innate immune response of CNS attenuates AD-like pathology (Bacher et al 2008; Walker and Lue 2007). Enhanced expression of MIF might contribute to the persistent activation of glial, chronic neuroinflammation and neurodegeneration. We investigated the effect of MIF on inflammatory markers and spatial learning in a mouse model of sporadic AD and on tau pathology in AD patients

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Conclusion