The Role of Galectin-3 in the Regulation of the Immune-Brain Response in Alzheimer's Disease and Frontotemporal Dementia

Abstract

Neurodegenerative pathologies such as Alzheimer's disease and frontotemporal dementia are two neurodegenerative processes that affect millions of people worldwide, generally in old age. Despite being discovered over a century ago, these pathologies lack not only an effective treatment capable of reversing the disease or significantly improving the quality of life of patients and, by extension, their families, but also a clear understanding of their origin, which remains an unresolved challenge for the scientific community. Both Alzheimer's disease and frontotemporal dementia are characterized by a marked presence of microglial cells in specific brain regions. This microglia exhibits a characteristic activation phenotype, in which galectin-3 (Gal3) plays a prominent role. Previous studies from our group have described how Gal3 acts as a ligand for TREM2, which is necessary to induce a shift in the microglial phenotype from homeostatic to reactive microglia. Furthermore, Gal3 has been proposed as a potential biomarker in some neurodegenerative diseases. In the present study, we investigated how the microglial response can modify some of the most relevant histopathological features in an animal model of Alzheimer's disease characterized by APP overexpression. Specifically, we evaluated how the absence of Gal3 can induce changes in the morphology and toxicity of ?-amyloid peptide plaques, one of the key pathological hallmarks of the disease. We observed that the absence of Gal3 leads to a modification in the microglial activation profile, with a reduction in the expression of certain characteristic markers. In this context, we highlight that the absence of Gal3 significantly attenuated the type I interferon signaling pathway, which is closely linked to disease progression and plays a key role in amyloid pathology. Additionally, our study demonstrates that the absence of Gal3 induced an increase of TREM2 in plaque-associated microglia, one of the most relevant microglial proteins in the context of Alzheimer's disease. Regarding frontotemporal dementia, this study employed a knockout animal model for the progranulin gene (PGRNKO). Our findings point to the thalamus and the thalamocortical tract as two of the most affected regions in this animal model. We describe how the absence of progranulin leads to the overexpression of genes associated with reactive microglia, with Gal3 being one of the most prominent alongside GPNMB. It has been reported that PGRNKO animals exhibit marked lysosomal dysfunction, positioning progranulin as an essential element for proper lysosomal homeostasis. Additionally, PGRNKO animals present severe neuronal ceroid lipofuscinosis, with the thalamus being one of the most affected areas. The presence of lipofuscin in these animals is not limited to neurons; rather, microglial cells, through the phagocytosis of lipofuscin-positive neurons, accumulate this lipid-rich substance in their lysosomes. Our transcriptomic analysis of the thalamic region reveals a marked enrichment of pathways associated with programmed cell death. Interestingly, in this doctoral thesis, we demonstrate that the absence of Gal3 significantly attenuates these pathways in the thalamus. Along these lines, our results show that Gal3 deletion significantly reduces lipofuscin accumulation in PGRNKO animals. This improvement in one of the most relevant histopathological features of the PGRNKO model is accompanied by a shift in the microglial phenotype in the thalamus, with a predominance of a less inflammatory environment. Finally, due to the high level of microglial reactivity in the absence of progranulin, we investigated whether this phenotypic change could alter the presence of hyperphosphorylated tau protein in the P301S animal model. We found that PGRNKO/P301S animals exhibit a lower accumulation of hyperphosphorylated tau protein in the hippocampus, reduced microgliosis in this region and behavioral alterations in the animals.