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

© 2021 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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 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.
This work was funded by the Fundação para a Ciência e Tecnologia (IF/00013/2014, LISBOA-01-0145-FEDER-028241, and PTDC/MED-IMU/1988/2020) to J.C.R., Santa Casa da Misericórdia (MB-7-2018) and Fundacão para a Ciência e Tecnologia (PTDC/BIM-MEC/4778/2014 and IF/00105/2012) to L.V.L., and PD/BD/114103/2015 to H.C.B. The ORCIDs for this article are as follows: 0000-0001-8367-3005 (L.V.L.) and 0000-0002-7852-343X (J.C.R.).