Microglial impact on tau pathology in the context of the proinflammatory mediator Galectin-3

Abstract

Neurodegenerative diseases are becoming an increasing social and economic burden worldwide. A subset of neurodegenerative diseases, called tauopathies, accumulate abnormally aggregated tau (a microtubule-binding protein) as one of their main pathological hallmarks. The role of microglia, the immune cells of the central nervous system, in tau pathology, has been increasingly discussed in the past years. Although microglia have been shown to be activated in tauopathies, the mechanisms that govern this activation have yet to be deciphered. Galectin-3 is a pro-inflammatory mediator of microglia that has been shown to be elevated in the presence of tau pathology both in mouse models and human tauopathy patients, rendering it a compelling target for further studies.
This thesis aims to evaluate how the knockout of Galectin-3 affects tau pathology and its related phenotypes in vivo and in vitro. Our study focuses on assessing differences in pathology burden, neurodegeneration and inflammation in tau-accumulating PS19 and PS19Gal3KO mice, as well as investigating the role of Galectin-3 in vitro using BV2 cells and N2A cells.
Our study shows a sex-specific effect of Gal-3’s knockout in female PS19 mice, which accumulate less abnormally conformed and phosphorylated tau in the hippocampus and cortex. We also observe decreased levels of total tau and phosphorylated tau in the hippocampus of PS19Gal3KO mice, but without any sex-specificity. We report no differences in synaptic or neuronal loss between 9-month-old PS19 and PS19Gal3KO mice, but we observe hypertrophy of cortical neurons bearing tau. We find elevated Gal-3 levels in the Prefrontal cortex of PS19 mice compared to WT mice, which correlate with specific tau phosphorylations but not with increased pro-inflammatory cytokines levels. In our in vitro experiments we confirm that BV2 cells are capable of uptaking and degrading tau pre-formed fibrils and we show a difference in highly aggregated intracellular tau between WT and Gal3KO cells. Lastly, we observe that the treatment of TauGFP-transfected N2A cells with Galectin-3 does not change their tau content.
Overall, the thesis’ aims have been met, but potential improvements and alternative methodologies are being explored.

Popular Abstract

Galectin-3: a key player in the modulation of tau pathology


Most of you have probably heard about neurodegenerative diseases. The reason why they are called “neurodegenerative” is that they cause the malfunction, and eventually death, of neurons, the brain cells that allow us to think, talk, walk and basically function as human beings. There is a group of neurodegenerative diseases that are called tauopathies, because they are characterized by the accumulation of a protein called tau inside neurons. Tau is a protein that is normally found in the brain and usually helps neurons to connect with each other, a fundamental characteristic that allows them to communicate. In tauopathies, however, this protein is modified and aggregated, making it toxic for the neurons bearing it. In a healthy brain, microglia (the immune cells of the brain) activate when they sense any change in the brain’s equilibrium, essentially eating and digesting the underlying cause. In tauopathies, microglia are chronically activated and the molecules that they produce seem to influence tau pathology. One of these molecules is Galectin-3 (Gal-3), which increases microglial activation. Since different research groups have shown that Gal-3 levels are elevated in tauopathy patients, we wanted to study if preventing its production affects tau pathology.



To do so, we used a mouse model called PS19, which accumulates mutated tau, and compared it to PS19 mice who have been modified to not produce Galectin-3 (Gal3KO). We studied the brains of these mice comparing the amount of tau pathology they carry, the degeneration and loss of neurons they suffer and the production of inflammatory molecules they exhibit. Another part of the project uses two different cell types: mouse microglial (BV2) and neuronal (N2A) cells. We studied the differences in tau uptake, degradation and aggregation in normal and Gal3KO BV2 cells and tau accumulation in human tau-producing N2A cells treated with Gal-3.


We observed that Gal3KO reduces tau pathology, potentially in a sex-specific manner and especially in the hippocampus. We did not report differences in neurodegeneration between any mouse strains, but observed an effect of tau accumulation on neurons, which seems to be swollen compared to healthy neurons. The amount of Gal-3 produced by PS19 mice was increased compared to healthy mice and correlated positively with specific modifications of tau but not with a higher production of inflammatory molecules. Finally, Gal3KO BV2 cells showed slight differences in tau processing compared to normal BV2 cells, while the accumulation of tau in N2A cells did not change when treated with Galectin-3.


This study shows that Gal-3 influences tau pathology, but more research is needed to understand the underlying mechanisms. A clearer understanding of how Gal-3 influences tau pathology could lead to the discovery of new therapeutic targets for the treatment of tauopathy patients.


Master’s Degree Project in Molecular Biology 60 credits 2024
Department of Biology, Lund University


Tomas Deierborg and Lluís Camprubí-Ferrer
Experimental neuroinflammation laboratory, Department of Experimental medical science

• author: Dell'eva, Marzia
• supervisor: Thomas Deierborg
• organization: Degree Projects in Molecular Biology
• course: MOBN03 20232
• year: 2024
• type: H2 - Master's Degree (Two Years)
• subject: Biology and Life Sciences
• language: English
• id: 9176117
• date added to LUP: 2024-10-04 13:24:17
• date last changed: 2024-10-04 13:24:17