Journal Article

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

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

2023

Overview

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. Obesity and aging increase Alzheimer’s disease (AD) risk. Here, using an AD mouse model and high-fat diet, we suggest that immune exhaustion links the two risk factors, and identify a metabolite that can hasten immune dysfunction and memory deficit.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/31 / 13/51 / 49/91 / 631/250/371 / 631/378/1689/1283 / 64/60 / 692/699/1702/393 / 692/699/375/365/1283 / Aging / Alzheimer Disease - metabolism / Alzheimer's disease / Animals / CD4 antigen / Cell proliferation / Deregulation / Diet / Diet, High-Fat - adverse effects / Disease Models, Animal / Gene sequencing / High fat diet / Hippocampus / Humanities and Social Sciences / Humans / Immunity / Immunological memory / Impairment / Lymphocytes / Lymphocytes T / Macrophages / Memory cells / Memory Disorders - etiology / Metabolites / Mice / Mice, Transgenic / multidisciplinary / N-Acetylneuraminic Acid / Neurodegenerative diseases / Obesity / Obesity - complications / Recognition / Risk factors / Science / Science (multidisciplinary) / Spleen