Figure - available from: Alzheimer's & Dementia
This content is subject to copyright. Terms and conditions apply.
Galectin‐3 levels in CSF (A, B, C) and serum (D, E, F). The p‐values of the plots were adjusted for multiple comparisons and corrected by age and sex. (A) CSF Gal‐3 levels in FTD cases are increased compared with controls. (B) Comparing FTD clinical syndromes, the bvFTD group showed higher levels of CSF Gal‐3 than controls, svPPA, and nfvPPA. (C) CSF Gal‐3 levels in mutation carriers revealed higher levels in MAPT carriers. (D) Serum levels of Gal‐3 were elevated in FTD patients. (E) Serum Gal‐3 levels between clinical syndromes showed higher levels in nfvPPA than in svPPA, with no differences in other comparisons. (F) No differences in serum Gal‐3 levels were found between mutation carriers. (See Section 2.6 for further statistical analysis description.)
Source publication
INTRODUCTION
Neuroinflammation is a major contributor to the progression of frontotemporal dementia (FTD). Galectin‐3 (Gal‐3), a microglial activation regulator, holds promise as a therapeutic target and potential biomarker. Our study aimed to investigate Gal‐3 levels in patients with FTD and assess its diagnostic potential.
METHODS
We examined Ga...
Citations
... This study suggests that inhibition of the activity of this protein leads to a significant reduction in the inflammatory response [32]. In another study investigating the role of Gal-3, a microglial marker, in the neurodegenerative mechanism of frontotemporal dementia (FTD), high levels of Gal-3 were found in the cerebrospinal fluid and serum of both sporadic and genetic FTD patients [106]. Gal-3 has also been shown to be upregulated in the brains of Alzheimer's patients and 5xFAD (familial Alzheimer's disease) mice and is expressed explicitly in microglia associated with amyloid beta (Aβ) plaques [104,107]. ...
Excitotoxicity caused by excessive concentration of the excitatory neurotransmitter glutamate causes neuronal cell death and promotes neurodegenerative disorders. The neuroexcitant neurotoxin kainic acid (KA) induces excitotoxicity, leading to neuronal death via oxidative stress and inflammation, and its experimental use is widespread. This study was designed to determine the protective effect of Troxerutin (TXR) and its relationship with Galectin-3 (Gal-3) in experimental excitotoxicity with neuroinflammation and oxidative stress. Fifty male Wistar rats were divided into five groups (n = 10): Control group rats received intraperitoneal (ip) normal saline for 6 days. Sham group rats received a single dose of intracerebroventricular (icv) normal saline on the first day. KA group rats were treated with a single dose of KA; icv-0.5 μg/μl). TXR group rats treated with TXR for 6 days: ip-100 mg/kg) and KA + TXR group rats treated with KA (single dose) and TXR (6 days). It was observed that malondialdehyde (MDA) and interleukin-1β (IL-1β) levels increased and reduced glutathione (GSH) levels decreased in the cerebral cortex of rats with KA neurotoxicity. TXR treatment caused a significant improvement in MDA and GSH levels and a significant decrease in IL-1β levels in rats with the excitotoxicity model. Gal-3 expressions in the hippocampus and cerebellum increased in KA-treated rats, whereas TXR treatment decreased Gal-3 expressions. In addition, histopathological changes caused by KA administration showed improvement in TXR-treated groups. In conclusion, the findings showed that TXR treatment attenuated KA-induced neurotoxicity by reducing oxidative tissue damage, inflammatory response and Gal-3 expression.
... In total, 15 biomarkers were measured in at least four studies, 14 in three studies, 55 in two studies, and 201 in only one study each. When comparing FTD patients with healthy controls (Table 1), the most substantial evidence for increased biomarker levels was found for glial fibrillary acidic protein (GFAP) in both blood [16][17][18][19][20][21][22][23][24][25] and CSF [21,[26][27][28][29]. Elevated CSF levels of YKL-40 (CHI3L1) [21,[29][30][31][32][33][34][35][36] and chitotriosidase-1 (CHIT1) [21,29,30,37] followed. Progranulin (PGRN) in blood showed the most evidence of decrease [38][39][40][41][42]. Additionally, four biomarkers-CCL19, CXCL1, CXCL6, and Somatostatin (SST)-were reported to have decreased levels in two studies each [43][44][45][46]. ...
... Immune markers such as GFAP, YKL-40, and CHIT1, which were consistently elevated in FTD compared to healthy controls, showed no significant differences across the major FTD phenotypes, suggesting their upregulation is a common feature of FTD. The only significantly altered biomarker was CSF Galectin-3, which was higher in bvFTD compared to svPPA and nfvPPA [32]. Galectin-3, predominantly expressed by microglia, plays a complex role in neuroinflammation, likely via the NF-KB pathway [150]. ...
... Galectin-3, predominantly expressed by microglia, plays a complex role in neuroinflammation, likely via the NF-KB pathway [150]. Interestingly, MAPT-FTD was the only genotype with significantly higher CSF Galectin-3 levels compared to C9ORF72and GRN-mediated FTD [32], and it also displayed the lowest CSF CHIT1 levels [30]. This suggests that in MAPT-FTD, microglial activity is more committed to Galectin-3-mediated phagocytosis and debris clearance, possibly driven by tau accumulation, over CHIT1-mediated inflammation and matrix remodeling. ...
Dysregulated immune activation plays a key role in the pathogenesis of neurodegenerative diseases, including frontotemporal dementia (FTD). This study reviews immunological biomarkers associated with FTD and its subtypes. A systematic search of PubMed and Web of Science was conducted for studies published before 1 January 2025, focusing on immunological biomarkers in CSF or blood from FTD patients with comparisons to healthy or neurological controls. A total of 124 studies were included, involving 6686 FTD patients and 202 immune biomarkers. Key findings include elevated levels of GFAP and MCP1/CCL2 in both CSF and blood and consistently increased CHIT1 and YKL-40 in CSF. Complement proteins from the classical activation pathway emerged as promising targets. Distinct immune markers were found to differentiate FTD from Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS), with GFAP, SPARC, and SPP1 varying between FTD and AD and IL-15, HERV-K, NOD2, and CHIT1 differing between FTD and ALS. A few markers, such as Galectin-3 and PGRN, distinguished FTD subtypes. Enrichment analysis highlighted IL-10 signaling and immune cell chemotaxis as potential pathways for further exploration. This study provides an overview of immunological biomarkers in FTD, emphasizing those most relevant for future research on immune dysregulation in FTD pathogenesis.
... A study conducted on patients with frontotemporal dementia found that increased Gal-3 levels were associated with cognitive decline in the disease. This finding suggests that Gal-3 may play a role in neuroinflammatory processes in patients with frontotemporal dementia and could be considered a biomarker and therapeutic target for this disease [37]. Another animal study investigated the role of Gal-3 in modulating anxiety levels. ...
Objectives: This study aimed to assess serum Galectin-3 (Gal-3) and IL-6 levels, along with other inflammatory markers, in type-1 bipolar disorder (BD) patients and explore their relationship with clinical features, metabolic parameters, and symptom severity. Background: The study included 38 manic, 35 euthymic BD patients, and 40 healthy controls. Sociodemographic data, such as age, gender, alcohol and smoking habits, and body mass index (BMI), were recorded. Methods: The Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HAM-D) were administered to patients. Biochemical measurements included Gal-3, IL-6, CRP, neutrophil, lymphocyte, platelet counts, and inflammatory indices like NLR, PLR, SII, and SIRI. Results: Gal-3 levels significantly differed among the groups (F = 52.251, p < 0.001), with the highest levels in euthymic patients. IL-6 levels were elevated in both manic and euthymic patients compared to controls (F = 7.379, p = 0.001). Manic patients had significantly higher levels of neutrophils, monocytes, CRP, NLR, PLR, SII, and SIRI. A positive correlation was found between Gal-3 levels, the total number of episodes, and YMRS scores in manic patients. In euthymic patients, Gal-3 levels correlated positively with disease duration and episode count. Conclusions: Elevated Gal-3 levels, particularly in the euthymic phase, may serve as a biomarker for BD and indicate ongoing inflammation. These findings suggest Gal-3 could help identify BD and differentiate the euthymic phase.
... Neuronal dysfunction/death, abnormal protein accumulation, and activation of the central immune system are the main factors in the pathological progression of FTD. Abnormal protein conformation and accumulation will activate the immune system, leading to neuroinflammation [49] . White matter hyperintensity usually reflects the abnormality of brain blood vessels and nerve tissues. ...
Frontotemporal dementia (FTD) is a very common type of neurodegenerative dementia and is the main cause of dementia in people under 65 years old. It has strong heritability. To explore whether there are urinary proteins and biological pathways that are different between those who have not been identified with FTD under existing diagnostic methods and healthy people, this study conducts urinary proteomics analysis on people without disease with a family history of FTD and healthy people. The results show that there are 387 significantly different proteins (P<0.01; FC≥2.0 or ≤0.5) between the two groups. Among them, many proteins have been reported to play a role in FTD or the nervous system. In particular, Progranulin (PGRN) is considered an effective biomarker for FTD. Among the 139 biological pathways enriched by differential proteins (P<0.01), there are many pathways directly related to neurons and the nervous system, including glial cells and microglia. The differences in urinary proteomes between people without disease with a family history of FTD and healthy people make urinary proteomics have the potential to provide clues in exploring potential FTD patient populations and exploring the mechanisms related to the early occurrence and development of FTD, opening up a new perspective for FTD prevention and early diagnosis.
... FTD and ALS exhibit common molecular pathological features, including the mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43), a ribonucleotide protein that regulates mRNA metabolism, the accumulation of FTD/ALS-associated mutated proteins in inclusions, and the failure of the PQC system [173,176,177]. FTD/ ALS are also associated with alterations to the autophagy-lysosomal pathway, detectable in postmortem tissue of FTD/ALS patients [87,178] and evidenced by increased levels of galectin-3 in the spinal cord and cerebrospinal fluid, suggesting changes in lysosome dynamics [178,179]. ...
Lysosomes are acidic organelles involved in crucial intracellular functions, including the degradation of organelles and protein, membrane repair, phagocytosis, endocytosis, and nutrient sensing. Given these key roles of lysosomes, maintaining their homeostasis is essential for cell viability. Thus, to preserve lysosome integrity and functionality, cells have developed a complex intracellular system, called lysosome quality control (LQC). Several stressors may affect the integrity of lysosomes, causing Lysosomal membrane permeabilization (LMP), in which membrane rupture results in the leakage of luminal hydrolase enzymes into the cytosol. After sensing the damage, LQC either activates lysosome repair, or induces the degradation of the ruptured lysosomes through autophagy. In addition, LQC stimulates the de novo biogenesis of functional lysosomes and lysosome exocytosis. Alterations in LQC give rise to deleterious consequences for cellular homeostasis. Specifically, the persistence of impaired lysosomes or the malfunctioning of lysosomal processes leads to cellular toxicity and death, thereby contributing to the pathogenesis of different disorders, including neurodegenerative diseases (NDs). Recently, several pieces of evidence have underlined the importance of the role of lysosomes in NDs. In this review, we describe the elements of the LQC system, how they cooperate to maintain lysosome homeostasis, and their implication in the pathogenesis of different NDs.
Graphical Abstract
... Em amostras corticais humanas com DA e em camundongos, um estudo observou regulação positiva e expressão significativa da gal-3 em células microgliais posicionadas próximas a placas de agregados extracelulares de peptídeo beta amilóide (βA), resultados não observados no grupo controle17 . Num estudo com amostras de tecido cortical de pacientes com demência frontotemporal, foi observado regulação positiva da gal-3, aumento significativo de níveis séricos e no LCR da gal-3 e correlação com a proteína tau18 . A ativação microglial promove mecanismos pró-inflamatórios no SNC, como a produção de citocinas e estresse oxidativo, que contribuem com processos neurodegenerativos. ...
Distúrbios neurológicos (DNs) têm crescido junto ao envelhecimento e aumento populacional global, sendo um desafio ao sistema de saúde pública. DNs envolvem disfunções sinápticas e moleculares que comprometem a cognição, memória e aprendizado. As galectinas (gal) são potenciais moduladoras da neuroinflamação, com expressão neurológica. Assim, tem-se como objetivo entender a associação entre as galectinas, vias moleculares e celulares na fisiopatologia de DNs. Realizou-se uma revisão narrativa nas bases de dados Pubmed, LILACS e Scielo, com as palavras-chave em inglês e português “galectins” and “cognition”. 23 estudos in vivo, in vitro e post-mortem foram incluídos nesta revisão. Na Doença de Alzheimer (DA), isquemia/reperfusão renal (IR), HIV, malária cerebral e esquizofrenia, diversos estudos mostraram relação entre expressão significativa aumentada ou reduzida da gal-3, gal-9, gal-8 e gal-1 e marcadores pró-inflamatórios e anti-inflamatórios, neurodegenerativos e sinápticos. Na DA, apneia obstrutiva do sono e IR, o silenciamento ou inibição farmacológica da gal-3 atenuou a neuroinflamação e apoptose neuronal, gerou proteção contra neurotoxicidade e melhorou o comprometimento cognitivo. Na isquemia a administração de gal-3 gerou remielinização e atenuação de déficits cognitivos. Concluiu-se que as galectinas –1, –3, -4, -8 e –9 modulam processos neuroinflamatórios e neurodegenerativos presentes em disfunções cognitivas de DNs, sendo potenciais alvos terapêuticos. Palavras-chave: galectinas; cognição; neurofisiologia; inflamação; mielina.
Activation of the innate immune system following pattern recognition receptor binding has emerged as one of the major pathogenic mechanisms in neurodegenerative disease. Experimental, epidemiological, pathological, and genetic evidence underscores the meaning of innate immune activation during the prodromal as well as clinical phases of several neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Importantly, innate immune activation and the subsequent release of inflammatory mediators contribute mechanistically to other hallmarks of neurodegenerative diseases such as aberrant proteostatis, pathological protein aggregation, cytoskeleton abnormalities, altered energy homeostasis, RNA and DNA defects, and synaptic and network disbalance and ultimately to the induction of neuronal cell death. In this review, we discuss common mechanisms of innate immune activation in neurodegeneration, with particular emphasis on the pattern recognition receptors (PRRs) and other receptors involved in the detection of damage-associated molecular patterns (DAMPs).
