Amyloid-β Homeostasis Bridges Inflammation, Synaptic Plasticity Deficits and Cognitive Dysfunction in Multiple Sclerosis.

Mario Stampanoni Bassi,Sara Garofalo,Diego Centonze,Jonny Di Giandomenico,Girolama A Marfia,Annamaria Finardi,Marianna Storto,Francesco Mori,Ilaria Simonelli,Giulia M Sancesario,Roberto Furlan,Ennio Iezzi,Luana Gilio

doi:10.3389/fnmol.2017.00390

Abstract

Cognitive deficits are frequently observed in multiple sclerosis (MS), mainly involving processing speed and episodic memory. Both demyelination and gray matter atrophy can contribute to cognitive deficits in MS. In recent years, neuroinflammation is emerging as a new factor influencing clinical course in MS. Inflammatory cytokines induce synaptic dysfunction in MS. Synaptic plasticity occurring within hippocampal structures is considered as one of the basic physiological mechanisms of learning and memory. In experimental models of MS, hippocampal plasticity is profoundly altered by proinflammatory cytokines. Although mechanisms of inflammation-induced hippocampal pathology in MS are not completely understood, alteration of Amyloid-β (Aβ) metabolism is emerging as a key factor linking together inflammation, synaptic plasticity and neurodegeneration in different neurological diseases. We explored the correlation between concentrations of Aβ1–42 and the levels of some proinflammatory and anti-inflammatory cytokines (interleukin-1β (IL-1β), IL1-ra, IL-8, IL-10, IL-12, tumor necrosis factor α (TNFα), interferon γ (IFNγ)) in the cerebrospinal fluid (CSF) of 103 remitting MS patients. CSF levels of Aβ1–42 were negatively correlated with the proinflammatory cytokine IL-8 and positively correlated with the anti-inflammatory molecules IL-10 and interleukin-1 receptor antagonist (IL-1ra). Other correlations, although noticeable, were either borderline or not significant. Our data show that an imbalance between proinflammatory and anti-inflammatory cytokines may lead to altered Aβ homeostasis, representing a key factor linking together inflammation, synaptic plasticity and cognitive dysfunction in MS. This could be relevant to identify novel therapeutic approaches to hinder the progression of cognitive dysfunction in MS.

Highlights

Cognitive deficits are common in Multiple Sclerosis (MS), affecting almost half of the patients and negatively influencing social functioning and quality of life (Rao et al, 1991; Benedict et al, 2006; Chiaravalloti and DeLuca, 2008)
Cognitive deficits in multiple sclerosis (MS) have been related to white matter damage, albeit hippocampal structures involvement is emerging as a key component of the cognitive dysfunction observed both in EAE and MS
The significant negative correlation between cerebrospinal fluid (CSF) Aβ1–42 concentrations and the proinflammatory cytokines IL-8 and IFNγ suggests that inflammatory response is associated to dysregulation of Aβ synthesis and degradation

Summary

INTRODUCTION

Cognitive deficits are common in Multiple Sclerosis (MS), affecting almost half of the patients and negatively influencing social functioning and quality of life (Rao et al, 1991; Benedict et al, 2006; Chiaravalloti and DeLuca, 2008). In EAE specific proinflammatory cytokines, including IL-1β and TNFα, alter both excitatory and inhibitory transmission resulting in synaptic hyperexcitability and excitotoxic neuronal damage (Centonze et al, 2009; Rossi et al, 2011; Mandolesi et al, 2013). CSF from MS patients in the active phase of disease reproduced in rodent brain slices both glutamatergic and GABAergic alterations and neuronal degeneration observed in EAE (Rossi et al, 2012a,b). There is evidence that anti-inflammatory cytokines may contribute to reduce synaptic hyperexcitability and neurodegeneration in MS patients (Rossi et al, 2011) Overall, these data suggest that synaptic alterations associated to neuroinflammation may represent a critical factor inducing neuronal dysfunction in MS

COGNITIVE DEFICITS IN MS AND EAE

SYNAPTIC PLASTICITY IN MS AND EAE

CONCLUSION

Findings

AUTHOR CONTRIBUTIONS