RT Journal Article
SR Electronic
T1 Accelerated cognitive decline in obese mouse model of Alzheimer’s disease is linked to sialic acid-driven immune deregulation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.05.479219
DO 10.1101/2022.02.05.479219
A1 Stefano Suzzi
A1 Tommaso Croese
A1 Adi Ravid
A1 Or Gold
A1 Abbe R. Clark
A1 Sedi Medina
A1 Daniel Kitsberg
A1 Miriam Adam
A1 Katherine A. Vernon
A1 Eva Kohnert
A1 Inbar Shapira
A1 Sergey Malitsky
A1 Maxim Itkin
A1 Sarah P. Colaiuta
A1 Liora Cahalon
A1 Michal Slyper
A1 Anna Greka
A1 Naomi Habib
A1 Michal Schwartz
YR 2022
UL http://biorxiv.org/content/early/2022/02/08/2022.02.05.479219.abstract
AB Systemic immunity supports healthy brain homeostasis. Accordingly, conditions causing systemic immune deregulation may accelerate onset of neurodegeneration in predisposed individuals. Here we show that, in the 5xFAD mouse model of Alzheimer’s disease (AD), high-fat diet-induced obesity accelerated cognitive decline, which was associated with immune deviations comprising increased splenic frequencies of exhausted CD4+ T effector memory cells and CD4+FOXP3+ regulatory T cells (Tregs). Non-targeted plasma metabolomics identified N-acetylneuraminic acid (NANA), the predominant sialic acid, as the major obesity-induced metabolite in 5xFAD mice, the levels of which directly correlated with Tregs abundance and inversely correlated with cognitive performance. Visceral adipose tissue macrophages were identified by sNuc-Seq as one potential source of NANA. Exposure to NANA led to immune deregulation in middle-aged wild-type mice, and ex vivo in human T cells. Our study identified diet-induced immune deregulation, potentially via sialic acid, as a previously unrecognized link between obesity and AD.Competing Interest StatementM. Schwartz is a consultant of ImmunoBrain Checkpoint LTD.