Galectin-3 as a central regulator of neuroinflammation and neurodegeneration
Camprubí-Ferrer, Lluís LU
(2026)
In Lund University, Faculty of Medicine Doctoral Dissertation Series
- Abstract
- Neuroinflammation emerges as a central driver of neurodegeneration, yet the molecular regulators orchestrating pathological microglial activation remain incompletely understood. This thesis investigates galectin-3 (Gal3), a glycan-binding protein with dual roles in microglial homeostasis and inflammatory signaling, as a master regulator linking neuroinflammation to proteinopathy progression in Alzheimer's disease (AD) and tauopathies. Integrating human cerebrospinal fluid (CSF) biomarker analysis, transgenic mouse models, and cellular mechanistic studies across four investigations, we demonstrate that Gal3 is markedly elevated in AD patient CSF and post-mortem tissue, with strongest correlations to tau pathology rather than amyloid-β (Aβ)... (More)
- Neuroinflammation emerges as a central driver of neurodegeneration, yet the molecular regulators orchestrating pathological microglial activation remain incompletely understood. This thesis investigates galectin-3 (Gal3), a glycan-binding protein with dual roles in microglial homeostasis and inflammatory signaling, as a master regulator linking neuroinflammation to proteinopathy progression in Alzheimer's disease (AD) and tauopathies. Integrating human cerebrospinal fluid (CSF) biomarker analysis, transgenic mouse models, and cellular mechanistic studies across four investigations, we demonstrate that Gal3 is markedly elevated in AD patient CSF and post-mortem tissue, with strongest correlations to tau pathology rather than amyloid-β (Aβ) burden. In AD cohorts, CSF Gal3 exhibits a biphasic association with cognitive performance, peaking at intermediate disease stages before declining alongside severe impairment, suggesting stagespecific microglial functionality transitions from protective containment to dystrophic exhaustion. Mechanistically, Gal3 exhibits dichotomous regulation: intracellular Gal3 maintains microglial quiescence, while extracellular Gal3 drives pro-inflammatory receptor clustering and pathological protein aggregate remodeling. In amyloid models, Gal3 promotes plaque compaction and dystrophic neurite formation; in tauopathy models, genetic ablation profoundly rescues pathology across multiple domainsreducing tau aggregation, restoring mitochondrial bioenergetics, preserving white matter integrity, and normalizing brain-wide transcriptomic dysregulation. These convergent findings position Gal3 as a therapeutic nexus uniquely positioned to simultaneously address neuroinflammation, protein aggregation, bioenergetic failure, and structural degeneration. With clinical-stage Gal3 inhibitors already in neurodegeneration trials, this work provides causal validation and mechanistic rationale for precision immune modulation. By reframing Gal3 as an integrative hub rather than isolated marker, these studies advance a unified model of tau-driven neurodegeneration and identify a clinically actionable target to shift disease trajectories toward resilience and delayed functional decline. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/7a5faf21-081c-43a5-b32b-f14a59f6dca0
- author
- Camprubí-Ferrer, Lluís
LU
- supervisor
- opponent
-
- MD, PhD Michael Heneka, Director of the Luxembourg Centre for Systems Biomedicine
- organization
- publishing date
- 2026
- type
- Thesis
- publication status
- published
- subject
- keywords
- Microglia, Galectin-3, Neuroinflammation, Neurodegeneration, Alzheimer's disease, Frontotemporal dementia
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2026:44
- pages
- 141 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Utblicken, Forum Medicum, BMC:E16003, Sölvegatan 19, Lund. Join by Zoom: https://lu-se.zoom.us/j/69209326687
- defense date
- 2026-03-27 13:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-842-9
- language
- English
- LU publication?
- yes
- id
- 7a5faf21-081c-43a5-b32b-f14a59f6dca0
- date added to LUP
- 2026-02-27 17:22:38
- date last changed
- 2026-03-09 12:49:03
@phdthesis{7a5faf21-081c-43a5-b32b-f14a59f6dca0,
abstract = {{Neuroinflammation emerges as a central driver of neurodegeneration, yet the molecular regulators orchestrating pathological microglial activation remain incompletely understood. This thesis investigates galectin-3 (Gal3), a glycan-binding protein with dual roles in microglial homeostasis and inflammatory signaling, as a master regulator linking neuroinflammation to proteinopathy progression in Alzheimer's disease (AD) and tauopathies. Integrating human cerebrospinal fluid (CSF) biomarker analysis, transgenic mouse models, and cellular mechanistic studies across four investigations, we demonstrate that Gal3 is markedly elevated in AD patient CSF and post-mortem tissue, with strongest correlations to tau pathology rather than amyloid-β (Aβ) burden. In AD cohorts, CSF Gal3 exhibits a biphasic association with cognitive performance, peaking at intermediate disease stages before declining alongside severe impairment, suggesting stagespecific microglial functionality transitions from protective containment to dystrophic exhaustion. Mechanistically, Gal3 exhibits dichotomous regulation: intracellular Gal3 maintains microglial quiescence, while extracellular Gal3 drives pro-inflammatory receptor clustering and pathological protein aggregate remodeling. In amyloid models, Gal3 promotes plaque compaction and dystrophic neurite formation; in tauopathy models, genetic ablation profoundly rescues pathology across multiple domainsreducing tau aggregation, restoring mitochondrial bioenergetics, preserving white matter integrity, and normalizing brain-wide transcriptomic dysregulation. These convergent findings position Gal3 as a therapeutic nexus uniquely positioned to simultaneously address neuroinflammation, protein aggregation, bioenergetic failure, and structural degeneration. With clinical-stage Gal3 inhibitors already in neurodegeneration trials, this work provides causal validation and mechanistic rationale for precision immune modulation. By reframing Gal3 as an integrative hub rather than isolated marker, these studies advance a unified model of tau-driven neurodegeneration and identify a clinically actionable target to shift disease trajectories toward resilience and delayed functional decline.}},
author = {{Camprubí-Ferrer, Lluís}},
isbn = {{978-91-8021-842-9}},
issn = {{1652-8220}},
keywords = {{Microglia; Galectin-3; Neuroinflammation; Neurodegeneration; Alzheimer's disease; Frontotemporal dementia}},
language = {{eng}},
number = {{2026:44}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Galectin-3 as a central regulator of neuroinflammation and neurodegeneration}},
url = {{https://lup.lub.lu.se/search/files/243499982/Thesis_Lluis_LUCRIS.pdf}},
year = {{2026}},
}