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

Abstract

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.

Galectin‐3 is upregulated in frontotemporal dementia patients with subtype specificity

“…Indeed, neuroinflammatory response has been linked to synaptic dysfunction 64 . We also demonstrated a positive relationship between CSF Gal‐3 levels and t‐tau in AD patients along with GAP‐43 and neurogranin, markers of synaptic dysfunction 24 . However, in this study no association was found between Gal‐3 and p‐tau 181, contrary to our previous study in AD patients where we observed a significant association 24 .…”

“…Our study also confirmed that Gal‐3 acts as an endogenous TREM2 ligand, a central player in the regulation of microglial activation under disease conditions 21 . It is important to note that in AD we found Gal‐3 in cerebrospinal fluid (CSF) to be strongly associated with neuroinflammation markers, synapse loss, and cognitive decline 24 . A recent study analyzing over 2000 human AD brain tissue samples identified a microglia module as a highly affected process in AD.…”

Neurodegeneration Markers Galectin-3 and Apolipoprotein E Are Elevated in the Aqueous Humor of Eyes With Glaucoma

“… 13 – 15 , 29 – 31 Recently, Gal-3 was identified as a cerebrospinal fluid biomarker in Alzheimer's disease which correlated with markers of neuronal degeneration, synaptic dysfunction, and neuroinflammation. 43 Gal-3 and Apoe are also upregulated in microglia in mouse models of glaucoma 19 and photoreceptor degeneration, 20 as well as in human postmortem glaucomatous tissues. 19 We therefore hypothesize that these molecules may be released from activated retinal microglia into the vitreous chamber, thereby reaching the anterior chamber of the eye.…”

Microglia dynamics in aging-related neurobehavioral and neuroinflammatory diseases

“…There are many studies leveraging the Gal-3’s pivotal role in AD pathophysiology [ 153 , 154 ]. Recent observational studies unraveled a substantial increase in the Gal-3’s serum and CSF level in AD cases compared to the control group [ 155 – 157 ]. An experiment conducted by Tao et al exhibited a concordant rise in Gal-3 and Aβ oligomerization in the frontal lobe of AD patients [ 158 ].…”