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.

Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden

Department of Biomedical and Biotechnological Sciences Anatomy Histology and Movement Sciences Section School of Medicine University of Catania Catania Italy

Department of Neurodegenerative Disease UCL Institute of Neurology London UK

Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden

Department of Psychiatry University of California San Diego La Jolla CA USA

Department of Translational Stem Cell Biology Research Institute of the Medical University of Varna Varna Bulgaria

International Clinical Research Center St Anne's University Hospital Brno Czech Republic

Neurologic Unit AOU Policlinico San Marco Department of Medical Surgical Sciences and Advanced Technologies GF Ingrassia University of Catania Catania Sicily Italy

UK Dementia Research Institute at UCL London UK

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Mayeux R, Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2(8):a006239 PubMed PMC

Gurwitz D. Auguste D and Alzheimer's disease. Lancet. 1997;350(9073):298. PubMed

Wang WY, et al. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann Transl Med. 2015;3(10):136. PubMed PMC

Medeiros R, LaFerla FM. Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol. 2013;239:133–138. PubMed

El Khoury JB, et al. CD36 mediates the innate host response to beta-amyloid. J Exp Med. 2003;197(12):1657–1666. PubMed PMC

Steardo L, Jr, et al. Does neuroinflammation turn on the flame in Alzheimer's disease? Focus on astrocytes. Front Neurosci. 2015;9:259. PubMed PMC

Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015;16(6):358–372. PubMed

Chen Y, et al. Interplay between microglia and Alzheimer's disease-focus on the most relevant risks: APOE genotype, sex and age. Front Aging Neurosci. 2021;13:631827. PubMed PMC

Schain M, Kreisl WC. Neuroinflammation in neurodegenerative disorders-a review. Curr Neurol Neurosci Rep. 2017;17(3):25. PubMed

Solito E, Sastre M. Microglia function in Alzheimer's disease. Front Pharmacol. 2012;3:14. PubMed PMC

Kanegawa N, et al. In vivo evidence of a functional association between immune cells in blood and brain in healthy human subjects. Brain Behav Immun. 2016;54:149–157. PubMed

Colombo E, Farina C. Astrocytes: key regulators of neuroinflammation. Trends Immunol. 2016;37(9):608–620. PubMed

Abbott NJ. Astrocyte-endothelial interactions and blood-brain barrier permeability. J Anat. 2002;200(6):629–638. PubMed PMC

Nagele RG, et al. Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 2003;971(2):197–209. PubMed

Henrissat B, Davies G. Structural and sequence-based classification of glycoside hydrolases. Curr Opin Struct Biol. 1997;7(5):637–644. PubMed

Eide KB, et al. The role of active site aromatic residues in substrate degradation by the human chitotriosidase. Biochim Biophys Acta. 2016;1864(2):242–247. PubMed

Bonneh-Barkay D, et al. Astrocyte and macrophage regulation of YKL-40 expression and cellular response in neuroinflammation. Brain Pathol. 2012;22(4):530–546. PubMed PMC

Di Rosa M, et al. Chitotriosidase and inflammatory mediator levels in Alzheimer's disease and cerebrovascular dementia. Eur J Neurosci. 2006;23(10):2648–2656. PubMed

Harris VK, Sadiq SA. Biomarkers of therapeutic response in multiple sclerosis: current status. Mol Diagn Ther. 2014;18(6):605–617. PubMed PMC

Varghese AM, et al. Chitotriosidase - a putative biomarker for sporadic amyotrophic lateral sclerosis. Clin Proteomics. 2013;10(1):19. PubMed PMC

Teitsdottir UD, et al. Cerebrospinal fluid C18 ceramide associates with markers of Alzheimer's disease and inflammation at the pre- and early stages of dementia. J Alzheimers Dis. 2021;81(1):231–244. PubMed PMC

Carter SF, et al. Astrocyte biomarkers in Alzheimer’s disease. Trends Mol Med. 2019;25(2):77–95. PubMed

Sanfilippo C, et al. Sex difference in CHI3L1 expression levels in human brain aging and in Alzheimer's disease. Brain Res. 2019;1720:146305. PubMed

Sanfilippo C, Malaguarnera L, Di Rosa M. Chitinase expression in Alzheimer's disease and non-demented brains regions. J Neurol Sci. 2016;369:242–249. PubMed

Sanfilippo C, et al. CHI3L2 Expression levels are correlated with AIF1, PECAM1, and CALB1 in the brains of Alzheimer’s disease patients. J Mol Neurosci. 2020;70(10):1598–1610. PubMed

Rehli M, et al. Transcriptional regulation of CHI3L1, a marker gene for late stages of macrophage differentiation. J Biol Chem. 2003;278(45):44058–44067. PubMed

Alcolea D, et al. Relationship between cortical thickness and cerebrospinal fluid YKL-40 in predementia stages of Alzheimer's disease. Neurobiol Aging. 2015;36(6):2018–2023. PubMed

Alcolea D, et al. Relationship between beta-secretase, inflammation and core cerebrospinal fluid biomarkers for Alzheimer's disease. J Alzheimers Dis. 2014;42(1):157–167. PubMed

Antonell A, et al. Cerebrospinal fluid level of YKL-40 protein in preclinical and prodromal Alzheimer's disease. J Alzheimers Dis. 2014;42(3):901–908. PubMed

Craig-Schapiro R, et al. YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer's disease. Biol Psychiatry. 2010;68(10):903–912. PubMed PMC

Melah KE, et al. Cerebrospinal fluid markers of Alzheimer's disease pathology and microglial activation are associated with altered white matter microstructure in asymptomatic adults at risk for Alzheimer's disease. J Alzheimers Dis. 2016;50(3):873–886. PubMed PMC

Querol-Vilaseca M, et al. YKL-40 (Chitinase 3-like I) is expressed in a subset of astrocytes in Alzheimer's disease and other tauopathies. J Neuroinflammation. 2017;14(1):118. PubMed PMC

Di Rosa M, et al. Evaluation of CHI3L-1 and CHIT-1 expression in differentiated and polarized macrophages. Inflammation. 2013;36(2):482–492. PubMed

Di Rosa M, et al. CHI3L1 nuclear localization in monocyte derived dendritic cells. Immunobiology. 2016;221(2):347–356. PubMed

Di Rosa M, et al. Determination of chitinases family during osteoclastogenesis. Bone. 2014;61:55–63. PubMed

Qiu QC, et al. CHI3L1 promotes tumor progression by activating TGF-beta signaling pathway in hepatocellular carcinoma. Sci Rep. 2018;8(1):15029. PubMed PMC

Litviakov N, et al. Expression of M2 macrophage markers YKL-39 and CCL18 in breast cancer is associated with the effect of neoadjuvant chemotherapy. Cancer Chemother Pharmacol. 2018;82(1):99–109. PubMed

Di Rosa M, et al. Prolactin induces chitotriosidase expression in human macrophages through PTK, PI3-K, and MAPK pathways. J Cell Biochem. 2009;107(5):881–889. PubMed

Sanfilippo C, et al. The chitinases expression is related to Simian Immunodeficiency Virus Encephalitis (SIVE) and in HIV encephalitis (HIVE) Virus Res. 2017;227:220–230. PubMed

Sanfilippo C, et al. CHI3L1 and CHI3L2 overexpression in motor cortex and spinal cord of sALS patients. Mol Cell Neurosci. 2017;85:162–169. PubMed

Wurm J, et al. Astrogliosis releases pro-oncogenic chitinase 3-like 1 causing MAPK signaling in glioblastoma. Cancers (Basel). 2019;11(10):1437. PubMed PMC

Mollgaard M, et al. Cerebrospinal fluid chitinase-3-like 2 and chitotriosidase are potential prognostic biomarkers in early multiple sclerosis. Eur J Neurol. 2016;23(5):898–905. PubMed

Malaguarnera L, et al. Action of prolactin, IFN-gamma, TNF-alpha and LPS on heme oxygenase-1 expression and VEGF release in human monocytes/macrophages. Int Immunopharmacol. 2005;5(9):1458–1469. PubMed

Castrogiovanni P, et al. Fasting and fast food diet play an opposite role in mice brain aging. Mol Neurobiol. 2018;55(8):6881–6893. PubMed

Sanfilippo C, et al. Middle-aged healthy women and Alzheimer's disease patients present an overlapping of brain cell transcriptional profile. Neuroscience. 2019;406:333–344. PubMed

Xiao J, Cao H, Chen J. False discovery rate control incorporating phylogenetic tree increases detection power in microbiome-wide multiple testing. Bioinformatics. 2017;33(18):2873–2881. PubMed

Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:Article3. PubMed

Davis S, Meltzer PS. GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics. 2007;23(14):1846–7. PubMed

Zuberi K, et al. GeneMANIA prediction server 2013 update. Nucleic Acids Res. 2013; 41(Web Server issue): W115-22. PubMed PMC

Szklarczyk D, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47(D1):D607–D613. PubMed PMC

Chang JT, Nevins JR. GATHER: a systems approach to interpreting genomic signatures. Bioinformatics. 2006;22(23):2926–2933. PubMed

Wang M, et al. Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer’s disease. Genome Med. 2016;8(1):104. PubMed PMC

Guijarro-Munoz I, et al. Lipopolysaccharide activates Toll-like receptor 4 (TLR4)-mediated NF-kappaB signaling pathway and proinflammatory response in human pericytes. J Biol Chem. 2014;289(4):2457–2468. PubMed PMC

Abbas AR, et al. Immune response in silico (IRIS): immune-specific genes identified from a compendium of microarray expression data. Genes Immun. 2005;6(4):319–331. PubMed

Castrogiovanni P, et al. Chitinase domain containing 1 increase is associated with low survival rate and M0 macrophages infiltrates in colorectal cancer patients. Pathol Res Pract. 2022;237:154038. PubMed

Rodwell GE, et al. A transcriptional profile of aging in the human kidney. PLoS Biol. 2004;2(12):e427. PubMed PMC

Sanfilippo C, et al. Hippocampal transcriptome deconvolution reveals differences in cell architecture of not demented elderly subjects underwent late-life physical activity. J Chem Neuroanat. 2021;113:101934. PubMed

Box GEP, Tiao GC. Bayesian Inference in Statistical Analysis. Addison-Wesley. 1992;1(1):603.

Cheadle C, et al. Analysis of microarray data using Z score transformation. J Mol Diagnostics JMD. 2003;5(2):73–81. PubMed PMC

Care MA, et al. A microarray platform-independent classification tool for cell of origin class allows comparative analysis of gene expression in diffuse large B-cell lymphoma. PLoS One. 2013;8(2):e55895. PubMed PMC

Wang J, et al. Differences in gene expression between B-cell chronic lymphocytic leukemia and normal B cells: a meta-analysis of three microarray studies. Bioinformatics. 2004;20(17):3166–3178. PubMed

Reddy TB, et al. TB database: an integrated platform for tuberculosis research. Nucleic Acids Res. 2009;37(Database issue):D499–D508. PubMed PMC

Le Cao KA, et al. YuGene: a simple approach to scale gene expression data derived from different platforms for integrated analyses. Genomics. 2014;103(4):239–251. PubMed

Chen QR, et al. An integrated cross-platform prognosis study on neuroblastoma patients. Genomics. 2008;92(4):195–203. PubMed PMC

Yasrebi H, et al. Can survival prediction be improved by merging gene expression data sets? PLoS One. 2009;4(10):e7431. PubMed PMC

Mehmood R, et al. Clustering by fast search and merge of local density peaks for gene expression microarray data. Sci Rep. 2017;7:45602. PubMed PMC

Cheadle C, et al. Application of z-score transformation to Affymetrix data. Appl Bioinforma. 2003;2(4):209–217. PubMed

Feng C, et al. Expression of Bcl-2 is a favorable prognostic biomarker in lung squamous cell carcinoma. Oncol Lett. 2018;15(5):6925–6930. PubMed PMC

Kang C, et al. Feature selection and tumor classification for microarray data using relaxed Lasso and generalized multi-class support vector machine. J Theor Biol. 2019;463:77–91. PubMed

Zetterberg H, et al. Neurofilaments in blood is a new promising preclinical biomarker for the screening of natural scrapie in sheep. PLoS One. 2019;14(12):e0226697. PubMed PMC

Zhang Z, et al. The appropriate marker for astrocytes: comparing the distribution and expression of three astrocytic markers in different mouse cerebral regions. Biomed Res Int. 2019;2019:9605265. PubMed PMC

Satoh J, et al. TMEM119 marks a subset of microglia in the human brain. Neuropathology. 2016;36(1):39–49. PubMed

Kenkhuis B, et al. Co-expression patterns of microglia markers Iba1, TMEM119 and P2RY12 in Alzheimer's disease. Neurobiol Dis. 2022;167:105684. PubMed

Castrogiovanni P, et al. Brain CHID1 Expression Correlates with NRGN and CALB1 in Healthy Subjects and AD Patients. Cells. 2021;10(4):882. PubMed PMC

Sanfilippo C, et al. Postsynaptic damage and microglial activation in AD patients could be linked CXCR4/CXCL12 expression levels. Brain Res. 2020;1749:147127. PubMed

Motta M, et al. Altered plasma cytokine levels in Alzheimer's disease: correlation with the disease progression. Immunol Lett. 2007;114(1):46–51. PubMed

Malaguarnera L, et al. Interleukin-18 and transforming growth factor-beta 1 plasma levels in Alzheimer's disease and vascular dementia. Neuropathology. 2006;26(4):307–312. PubMed

Catrogiovanni P, et al. The expression levels of CHI3L1 and IL15Ralpha correlate with TGM2 in duodenum biopsies of patients with celiac disease. Inflamm Res. 2020;69(9):925–935. PubMed

Sanfilippo C, et al. OAS Gene family expression is associated with HIV-related neurocognitive disorders. Mol Neurobiol. 2018;55(3):1905–1914. PubMed

Di Rosa M, et al. Immunoproteasome genes are modulated in CD34(+) JAK2(V617F) mutated cells from primary myelofibrosis patients. Int J Mol Sci. 2020;21(8):2926. PubMed PMC

Di Rosa M, et al. Different pediatric brain tumors are associated with different gene expression profiling. Acta Histochem. 2015;117(4-5):477–485. PubMed

Lomiguen C, et al. Possible role of chitin-like proteins in the etiology of Alzheimer's disease. J Alzheimers Dis. 2018;66(2):439–444. PubMed

Hong S, et al. TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels. Alzheimers Dement. 2021;17(10):1628–1640. PubMed

Lananna BV, et al. Chi3l1/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer's disease pathogenesis. Sci Transl Med. 2020;12(574):eaax3519. PubMed PMC

Hinsinger G, et al. Chitinase 3-like proteins as diagnostic and prognostic biomarkers of multiple sclerosis. Mult Scler. 2015;21(10):1251–1261. PubMed

Connolly K, et al. Potential role of chitinase-3-like protein 1 (CHI3L1/YKL-40) in neurodegeneration and Alzheimer’s disease. Alzheimers Dement. 2022;10.1002/alz.12612. PubMed PMC

Clarke LE, et al. Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci U S A. 2018;115(8):E1896–E1905. PubMed PMC

Moreno-Rodriguez M, et al. Frontal cortex chitinase and pentraxin neuroinflammatory alterations during the progression of Alzheimer’s disease. J Neuroinflammation. 2020;17(1):58. PubMed PMC

Matute-Blanch C, et al. Chitinase 3-like 1 is neurotoxic in primary cultured neurons. Sci Rep. 2020;10(1):7118. PubMed PMC

Liddelow SA, Barres BA. Reactive astrocytes: production, function, and therapeutic potential. Immunity. 2017;46(6):957–967. PubMed