N-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer’s disease mouse model

Stefano Suzzi*, Tommaso Croese, Adi Ravid, Or Gold, Abbe R. Clark, Sedi Medina, Daniel Kitsberg, Miriam Adam, Katherine A. Vernon, Eva Kohnert, Inbar Shapira, Sergey Malitsky, Maxim Itkin, Alexander Brandis, Tevie Mehlman, Tomer M. Salame, Sarah P. Colaiuta, Liora Cahalon, Michal Slyper, Anna Greka*Naomi Habib*, Michal Schwartz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Systemic immunity supports lifelong brain function. Obesity posits a chronic burden on systemic immunity. Independently, obesity was shown as a risk factor for Alzheimer’s disease (AD). Here we show that high-fat obesogenic diet accelerated recognition-memory impairment in an AD mouse model (5xFAD). In obese 5xFAD mice, hippocampal cells displayed only minor diet-related transcriptional changes, whereas the splenic immune landscape exhibited aging-like CD4+ T-cell deregulation. Following plasma metabolite profiling, we identified free N-acetylneuraminic acid (NANA), the predominant sialic acid, as the metabolite linking recognition-memory impairment to increased splenic immune-suppressive cells in mice. Single-nucleus RNA-sequencing revealed mouse visceral adipose macrophages as a potential source of NANA. In vitro, NANA reduced CD4+ T-cell proliferation, tested in both mouse and human. In vivo, NANA administration to standard diet-fed mice recapitulated high-fat diet effects on CD4+ T cells and accelerated recognition-memory impairment in 5xFAD mice. We suggest that obesity accelerates disease manifestation in a mouse model of AD via systemic immune exhaustion.

Original languageAmerican English
Article number1293
JournalNature Communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

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© 2023, The Author(s).

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