Venue: Centre Broca
Ana Victoria Prádanos
Maria Llorens’ lab
Centro de Biologia Molecular Severo Ochoa (CBMSO)
Madrid, Spain
Invited by Monica Fernandez Monreal (BIC) and Emilie Pacary (Neurocentre Magendie)
Title
Neurogenic niche dysfunction in a mouse model of alzheimer’s disease: a longitudinal analysis of glial and vascular alterations
Abstract
In the hippocampal dentate gyrus (DG), adult hippocampal neurogenesis (AHN) occurs within a specialized environment, the neurogenic niche, comprising an extensive vascular network and glial cells. This study aims to identify the cellular mechanisms underlying AHN failure in Alzheimer’s disease (AD) by longitudinally studying the components of the DG neurogenic niche.
We used a mouse model of AD (mice that overexpress glycogen synthase kinase 3 beta (GSK-3β)), and conducted a longitudinal study at 4, 12, 18, and 30 months of age (mo). Our results reveal significant alterations in glial populations and vascularization. In AD mice, astrocyte and microglia densities increase in the granule cell layer (GCL) at 4 mo but decrease in the subgranular zone (SGZ) by 12 mo, accompanied by morphological changes observed through 3D reconstructions. Oligodendrocyte precursor cells (OPCs) decrease in the GCL at 4 mo, while mature oligodendrocytes remain stable in the GCL but decline in the SGZ from 12 mo onwards. These glial changes correlate with increased DG vascularization, particularly in the SGZ at 12 and 18 mo and the GCL at 12 mo. GCL blood vessels exhibit increased thickness at 12 and 30 mo, with elevated CD31 immunoreactivity at 30 mo.
The putative interaction of newborn dentate granule cells with glial cells was also examined. Astrocytes show increased overlapping with 1-week-old neurons in the AD model, which decreases in 8-week-old neurons in both AD and wild-type conditions. Conversely, overlap with UEA1+ blood vessels increases in 8-week-old neurons compared to 1-week-old ones in AD mice.
Finally a detailed analysis of the hippocampal expression of 96 cytokines revealed a variable imbalance between pro- and anti-inflammatory signals in the AD model. These findings bring to light the disruption of the DG neurogenic niche homeostasis in this mouse model of AD, potentially contributing to AHN impairments.