New research published in Alzheimer’s and dementia found that differences in microglial “endophenotypes of immunometabolism,” defined by interactions between immune and metabolic responses in the brain, may contribute to the pathogenesis and progression of Alzheimer’s disease (AD) in women.1
Although women account for a higher proportion of AD cases than men, little is known about the genetic basis underlying sex-specific manifestations of AD. To complement the lack of knowledge on the subject, researchers have sought to evaluate the molecular mechanisms that contribute to gender differences, particularly female predominance, in the prevalence, symptomatology, and pathology of AD.
Investigators performed multimodal integration of clinical (i.e., neuropathological diagnostic scores, apolipoprotein E genotypes) and multi-omics (including metabolomics and global and snRNA-seq data) data on 469 subjects humans from the Religious Order Study and Rush Memory and Aging Project cohort with matched clinical, brain metabolomics, and whole brain transcriptome data: 324 women aged 88 ± 4 years and 145 men aged 87 ± 4 years , respectively.
Altered immunometabolism was investigated using 2 multi-omics datasets, including one that integrated bulk brain metabolomics and transcriptomics data to inspect sex differences in metabolite-association networks. immune gene, and another that integrated snRNA-seq data to assess sex difference in immune-metabolic system. the activity of metabolic pathways and cell-cell communication networks.
Clinical diagnosis of cognitive status at death was used to define AD phenotypes, and Braak staging and AD Registry Consortium scores were used to define AD phenotypes. progression of AD.
The investigators observed sex-specific alterations at the whole-brain and single-cell level, including sex-differential metabolites (e.g., N-acetylglutamate, GPC, 1-stearoyl-2-oleoyl-GPE (18:0/18 :1)) and associated immune genes (P2RX7, PTPN5, PAK1, TRIM5) in the brain context region. These alterations further included sex differences associated with the activity of metabolic and immune pathways in 7 cell types, such as elevated CLR pathway activity and reduced glutamate and glutamine metabolism in the microglia, as well as glutamate-mediated cell-cell communications in women in AD, such as a decrease in markers. communications between ex-neurons and microglia enabled by glutamic acid in female subjects.
Other findings included those that observed elevated interleukin (IL)-10 signaling activity by microglia and astrocytes in women with AD compared to controls. The investigators noted that since blocking IL-10 anti-inflammatory pathways has previously been shown to improve phagocytic microglia activity and limit brain amyloidosis in mouse models of AD, the Taking into account sex-specific differences in anti-inflammatory IL-10 responses could be useful when developing future treatments. strategies for AD.
The study results further revealed that heterogeneities in immunometabolism endophenotypes exhibited a sex-specific pattern in AD according to metabolites, pathways, and cell types. Results like the one that showed decreased abundance of N-acetylglutamate and N-acetyl-aspartyl-glutamate observed in 10,000 propensity score-matched cohorts in women with AD provide preliminary evidence that N -acetylglutamate may act as a potential sex-specific biomarker for AD.
Based on the study results, the researchers concluded that sex-specific differences in the regulation of immunometabolism play a crucial role in determining the sex-specific biological manifestations of AD, especially when they appear in a manner specific to microglia.
Immunometabolism, a relatively new area of study, holds promise for advancing research into neurodegenerative diseases like AD, especially as it is no longer considered exclusively a disease of the central nervous system. Further research into immunometabolism associated with AD prevalence may shape the development of treatments, clinical trials, and treatments for AD patients.
“At its core, Alzheimer’s disease is a health problem that affects women. To address this, we need to understand how biological sex contributes to the underpinnings of this disease,” said Jessica Caldwell, PhD, director of the Women’s Alzheimer’s Movement Prevention Center at the Cleveland Clinic and co-author of the paper, in A press release.2 “These results confirm that we need to examine gender differences in how the body and brain systems communicate to truly provide women with personalized care and we look forward to continuing this research.” »
