Improvement of cognitive function in wild-type and Alzheimer´s disease mouse models by the immunomodulatory properties of menthol inhalation or by depletion of T regulatory cells
Noelia Casares1*†, María Alfaro1†, Mar Cuadrado-Tejedor2,3, Aritz Lasarte-Cia1, Flor Navarro1, Isabel Vivas4, María Espelosin2, Paz Cartas-Cejudo5, Joaquín Fernández-Irigoyen5, Enrique Santamaría5, Ana García-Osta2‡ and Juan José Lasarte1*‡
A complex network of interactions exists between the olfactory, immune, and central nervous systems. In this work, we intend to investigate this connection using an immunostimulatory odorant like menthol, analyzing its impact on the immune system and the cognitive capacity in healthy and Alzheimer’s Disease Mouse Models. We first found that repeated short exposures to menthol odor enhanced the immune response against ovalbumin immunization.
Menthol inhalation also improved the cognitive capacity of immunocompetent mice but not in immunodeficient NSG mice, which exhibited very poor fear-conditioning. This improvement was associated with a downregulation of IL-1β and IL-6 mRNA in the brain´s prefrontal cortex, and it was impaired by anosmia induction with methimazole. Exposure to menthol for six months (1 week per month) prevented the cognitive impairment observed in the APP/PS1 mouse model of Alzheimer's. Besides, this improvement was also observed by the depletion or inhibition of T regulatory cells. Treg depletion also improved the cognitive capacity of the APPNL-G-F/NL-G-F Alzheimer´s mouse model. In all cases, improving learning capacity was associated with a downregulation of IL-1β mRNA. Blockade of the IL-1 receptor with anakinra significantly increased cognitive capacity in healthy mice and in the APP/PS1 model of Alzheimer´s disease.
These data suggest an association between the immunomodulatory capacity of smells and their impact on the cognitive functions of the animals, highlighting the potential of odors and immune modulators as therapeutic agents for CNS-related diseases.
Keywords: Alzheimer´s disease; Treg cells; central nervous system; cognitive capacity; immunomodulation; menthol; methimazole; olfactory system.
CITA DEL ARTÍCULO Front. Immunol., 27 April 2023 vol. 14. Doi: https://doi.org/10.3389/fimmu.2023.1130044