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- Sanfilippo, C., et al.
(författare)
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A sex-stratified analysis of neuroimmune gene expression signatures in Alzheimer's disease brains
- 2023
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Ingår i: Geroscience. - : Springer Science and Business Media LLC. - 2509-2715 .- 2509-2723. ; 45:1, s. 523-541
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is the most common form of progressively disabling dementia. The chitinases CHI3L1 and CHI3L2 have long been known as biomarkers for microglial and astrocytic activation in neurodegeneration. Here, we collected microarray datasets from the National Center for Biotechnology Information (NCBI) brain samples of non-demented controls (NDC) (n = 460), and of deceased patients with AD (n = 697). The AD patients were stratified according to sex. Comparing the high CHI3L1 and CHI3L2 expression group (75th percentile), and low CHI3L1 and CHI3L2 expression group (25th percentile), we obtained eight signatures according to the sex of patients and performed a genomic deconvolution analysis using neuroimmune signatures (NIS) belonging to twelve cell populations. Expression analysis revealed significantly higher CHI3L1 and CHI3L2 expression in AD compared with NDC, and positive correlations of these genes with GFAP and TMEM119. Furthermore, deconvolution analysis revealed that CHI3L1 and CHI3L2 high expression was associated with inflammatory signatures in both sexes. Neuronal activation profiles were significantly activated in AD patients with low CHI3L1 and CHI3L2 expression levels. Furthermore, gene ontology analysis of common genes regulated by the two chitinases unveiled immune response as a main biological process. Finally, microglia NIS significantly correlated with CHI3L2 expression levels and were more than 98% similar to microglia NIS determined by CHI3L1. According to our results, high levels of CHI3L1 and CHI3L2 in the brains of AD patients are associated with inflammatory transcriptomic signatures. The high correlation between CHI3L1 and CHI3L2 suggests strong co-regulation.
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| 2. |
- Sanfilippo, C., et al.
(författare)
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Sex difference in CHI3L1 expression levels in human brain aging and in Alzheimer's disease
- 2019
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Ingår i: Brain Research. - : Elsevier BV. - 0006-8993. ; 1720
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Tidskriftsartikel (refereegranskat)abstract
- Several genetic sexual dimorphisms have been identified in animal and human brains, which may form a neural basis for sex-specific predisposition to neurological diseases. In the last years, clinical studies have observed that Alzheimer's disease (AD) disproportionately affects women compared with men. Chitinase-3-Like 1 protein (CHI3L1) has been frequently investigated in body fluids as a surrogate marker of neuroinflammation in AD and other neurological disorders. Nevertheless, the sex-related differences in CHI3L1 expression in the human brain has not yet been investigated. Here we aimed to evaluate the specificity of increase of CHI3L1 in five brain regions (cerebellum, dorsolateral prefrontal cortex, prefrontal cortex, hippocampus, and visual cortex) of male and female controls during normal aging, as well as in AD patients. We selected ten microarray datasets from NCBI, representing normal aging (n = 1290) and AD (n = 992), and stratified the brain specimens according to age, gender and brain region. The expression levels of CHI3L1 were correlated with age and gender. Female control brain specimens showed higher CHI3L1 expression than male brains. The expression differences between men and women were most obvious in older subjects. The expression analysis of CHI3L1 in the different brain regions of AD subjects also showed sex differences; females with AD had greater expression in the cerebellum than males. Notably, sex-associated CHI3L1 expression differences in hippocampus disappeared in AD. These findings demonstrate that the expression of CHI3L1 in the brains of cognitively unimpaired subjects and AD patients is closely linked to age and sex, which was most obvious in the cerebellum. Further studies are needed to confirm our results.
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