The effects of Galectin-3 on hippocampal neurogenesis and neuroinflammation

Thesis

Galectin-3 (Gal-3) is upregulated in Alzheimer’s Disease (AD) patients and has been shown to contribute to Beta-amyloid (Aβ) deposition in mouse models of Alzheimer’s Disease. Genetic removal of Gal-3 in these models have shown reduction in plaque load and rescue of cognitive deficits. In the subventricular zone (SVZ), Gal-3 regulate postnatal gliogenesis and migration of neural progenitors through the rostral migratory stream. However, less is known about the effects of Gal-3 on hippocampal neurogenesis. In my thesis, I firstly show that Gal-3 is present in the hippocampus and its neurogenic subgranular zone (SGZ) in healthy adult mice. I then show in vitro that Gal-3 decreases neural stem cell proliferation without affecting their differentiation. However, genetic ablation of Gal-3 did not significantly affect hippocampal neurogenesis in healthy adult mice. Next, I show that Gal-3 knockout altered hippocampal microglial morphology in healthy adult mice but did not affect expression of disease associated microglial genes in vitro. However, Gal-3 increased expression of disease associated astrocytic genes by astrocytes. Functionally, Gal-3 increased microglial phagocytosis of Aβ, but only when co-cultured with astrocytes. I show that this was due to Gal-3 increasing astrocytic secretion of amyloid degrading enzymes including Matrix metalloproteinase 9 (MMP9). Lastly, I show that intrahippocampal coinjections of truncated Gal-3 without the oligomerisation domain (Gal-3C) with Aβ managed to induce Aβ deposits, but I also show that this was due to host upregulation of full length Gal-3. Hence showing that Gal-3C was not sufficient to induce Aβ deposition. I then show that this was likely due to the fact that only full length Gal-3 could promote high molecular weight oligomers of Aβ. In conclusion, my thesis provides insight into the effects of Gal-3 on hippocampal neurogenesis and on Aβ clearance by glial cells.

Authors: Ong, J

• DOI: 10.5287/ora-r1gppv6m7
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English