IL-17 triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer's disease.

Helena C Brigas,David Blum,Julie Darrigues,Afonso Antunes De Almeida,Kevin Carvalho,Miguel Ribeiro,Julie C Ribot,Luísa V Lopes,Hélène Marie,Bruno Silva-Santos,Victoria Gomez-Murcia,Emilie Faivre,Luc Buée,Sara Costa-Pereira,Jade Dunot,Paula A Pousinha,Rui Gomes,Joana E Coelho

doi:10.1016/j.celrep.2021.109574

Abstract

Neuroinflammation in patients with Alzheimer's disease (AD) and related mouse models has been recognized for decades, but the contribution of the recently described meningeal immune population to AD pathogenesis remains to be addressed. Here, using the 3xTg-AD model, we report an accumulation of interleukin-17 (IL-17)-producing cells, mostly γδ Tcells, in the brain and the meninges of female, but not male, mice, concomitant with the onset of cognitive decline. Critically, IL-17 neutralization into the ventricles is sufficient to prevent short-term memory and synaptic plasticity deficits at early stages of disease. These effects precede blood-brain barrier disruption and amyloid-beta or tau pathology, implying an early involvement of IL-17 in AD pathology. When IL-17 is neutralized at later stages of disease, the onset of short-memory deficits and amyloidosis-related splenomegaly is delayed. Altogether, our data support the idea that cognition relies on a finely regulated balance of "inflammatory" cytokines derived from the meningeal immune system.

Highlights

Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disorder characterized by cognitive deficits due to synaptic dysfunction and sequential formation of amyloid-beta (Ab) plaques and hyperphosphorylated tau tangles
IL-17+ cells accumulate in the central nervous system (CNS) at the onset of cognitive decline in 3xTg-AD mouse model An increase of IL-17 levels in the serum has been linked to disease progression in patients with AD (Chen et al, 2014)
To investigate the role of IL-17 in neuropathological changes and memory deficits associated with the early onset of AD, we used the triple-transgenic mouse model of AD (3xTg-AD), a progressive model of the disease developing both amyloid plaques and neurofibrillary tangles (Oddo et al, 2003b)

Summary

Introduction

Alzheimer’s disease (AD) is a highly prevalent neurodegenerative disorder characterized by cognitive deficits due to synaptic dysfunction and sequential formation of amyloid-beta (Ab) plaques and hyperphosphorylated tau tangles. The role of the immune system is not limited to the brain parenchyma, as it comprises complex interactions between the central nervous system (CNS) and the peripheral systems (Louveau et al, 2015). Immune cells and their soluble mediators, namely cytokines, play a key role in CNS function by modulating neuronal connectivity and impacting on sensory function (Chen et al, 2017), social behavior (Filiano et al, 2016), as well as learning and memory (Derecki et al, 2010; Monteiro et al, 2016; Ribeiro et al, 2019). It was recently shown that, upon aging and in AD, meningeal lymphatic vasculature deteriorates, impairing cognition (Da Mesquita et al, 2018). The role of specific meningeal immune populations and their molecular mediators in the context of AD was never addressed

Results

Discussion

Conclusion