Brigas HC, Ribeiro M, Coelho JE, Gomes R, Gomez-Murcia V, Carvalho K, Faivre E, Costa-Pereira S, Darrigues J, de Almeida AA, Buée L, Dunot J, Marie H, Pousinha PA, Blum D, Silva-Santos B, Lopes LV, Ribot JC. IL-17 triggers the onset of cognitive and synaptic deficits in early stages of Alzheimer's disease. Cell Rep. 2021 Aug 31;36(9):109574. PubMed.
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Instituto de Medicina Molecular, Fac Medicine Lisbon
The brain has long been considered to be a site of immune privilege; however, it is now increasingly appreciated that immune cells can enter the brain at steady state to exert important physiological effects. In a recent paper (Ribeiro et al, 2019), we described a distinctive population of Vγ6+ γδ T cells in the mouse meninges but not in the brain parenchyma, that support synaptic plasticity and short-term spatial memory acquisition. These cells are derived from the fetus, are present perinatally, and do not require the presence of microbiota or inflammatory signals for their maintenance in the meninges. Phenotypically, these γδ T cells are the pre-eminent producers of the cytokine IL-17 within the meninges but almost wholly lack production of the cytokine IFN-γ. Moreover, we know that γδ IL-17 T cells predominate at the early stages of inflammatory responses, and have the potential to orchestrate protective or detrimental crosstalk between the innate and adaptive immune compartments as shown in multiple sclerosis, stroke, and Parkinson’s disease.
However, the question of whether these meningeal-resident γδ IL-17 producing T cells have a role in a chronic neuroinflammatory setting such as Alzheimer’s disease remained unexplored.
Here, using the 3xTg-AD model, we report an accumulation of interleukin-17 (IL-17)-producing cells, mostly γδ T cells, 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.
Further studies could lead to the use of IL-17 as a biomarker of early stages, improving Alzheimer’s disease diagnosis.
References:
Ribeiro M, Brigas HC, Temido-Ferreira M, Pousinha PA, Regen T, Santa C, Coelho JE, Marques-Morgado I, Valente CA, Omenetti S, Stockinger B, Waisman A, Manadas B, Lopes LV, Silva-Santos B, Ribot JC. Meningeal γδ T cell-derived IL-17 controls synaptic plasticity and short-term memory. Sci Immunol. 2019 Oct 11;4(40) PubMed.
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