Galectin-3 is elevated in CSF and is associated with Aβ deposits and tau aggregates in brain tissue in Alzheimer’s disease

• Published in: Acta neuropathologica Vol. 144; no. 5; pp. 843 - 859
• Main Authors: Boza-Serrano, Antonio, Vrillon, Agathe, Minta, Karolina, Paulus, Agnes, Camprubí-Ferrer, Lluís, Garcia, Megg, Andreasson, Ulf, Antonell, Anna, Wennström, Malin, Gouras, Gunnar, Dumurgier, Julien, Cognat, Emmanuel, Molina-Porcel, Laura, Balasa, Mircea, Vitorica, Javier, Sánchez-Valle, Raquel, Paquet, Claire, Venero, Jose Luis, Blennow, Kaj, Deierborg, Tomas
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.11.2022; Springer Nature B.V
• Subjects: Age; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animal models; Animals; Basic Medicine; beta-Galactosidase - metabolism; Biomarkers; Biomarkers - cerebrospinal fluid; Brain - pathology; Central nervous system; Cerebrospinal fluid; Chitinase-3-Like Protein 1 - metabolism; Galectin 3; GAP-43 protein; GAP-43 Protein - metabolism; Glial fibrillary acidic protein; Hippocampus; Humans; Immunohistochemistry; Inflammation; Medical and Health Sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Medicinska och farmaceutiska grundvetenskaper; Mice; microglia; Microglial cells; Neurodegeneration; Neurodegenerative diseases; Neurogranin; Neurosciences; Neurosciences & Neurology; Neurovetenskaper; Original Paper; Pathology; pathway; Plaque, Amyloid - pathology; Principal components analysis; receptor; Senile plaques; strem2; Tau protein; tau Proteins - metabolism; β-Amyloid; β-Galactosidase
• DOI: 10.1007/s00401-022-02469-6
• ISSN: 0001-6322; 1432-0533

Galectin-3 (Gal-3) is a beta-galactosidase binding protein involved in microglial activation in the central nervous system (CNS). We previously demonstrated the crucial deleterious role of Gal-3 in microglial activation in Alzheimer’s disease (AD). Under AD conditions, Gal-3 is primarily expressed by microglial cells clustered around Aβ plaques in both human and mouse brain, and knocking out Gal-3 reduces AD pathology in AD-model mice. To further unravel the importance of Gal-3-associated inflammation in AD, we aimed to investigate the Gal-3 inflammatory response in the AD continuum. First, we measured Gal-3 levels in neocortical and hippocampal tissue from early-onset AD patients, including genetic and sporadic cases. We found that Gal-3 levels were significantly higher in both cortex and hippocampus in AD subjects. Immunohistochemistry revealed that Gal-3+ microglial cells were associated with amyloid plaques of a larger size and more irregular shape and with neurons containing tau-inclusions. We then analyzed the levels of Gal-3 in cerebrospinal fluid (CSF) from AD patients ( n  = 119) compared to control individuals ( n  = 36). CSF Gal-3 levels were elevated in AD patients compared to controls and more strongly correlated with tau (p-Tau181 and t-tau) and synaptic markers (GAP-43 and neurogranin) than with amyloid-β. Lastly, principal component analysis (PCA) of AD biomarkers revealed that CSF Gal-3 clustered and associated with other CSF neuroinflammatory markers, including sTREM-2, GFAP, and YKL-40. This neuroinflammatory component was more highly expressed in the CSF from amyloid-β positive (A+), CSF p-Tau181 positive (T+), and biomarker neurodegeneration positive/negative (N+/−) (A + T + N+/−) groups compared to the A + T−N− group. Overall, Gal-3 stands out as a key pathological biomarker of AD pathology that is measurable in CSF and, therefore, a potential target for disease-modifying therapies involving the neuroinflammatory response.