Astrocyte and Microglia: temporal changes in relation to β-amyloid plaques in an Alzheimer’s disease rat model

In Alzheimer's disease (AD), glial and neuronal alterations have been described. Using an AD rat model (McGill-R-Thy1-APP), we investigated astroglial and microglial changes across different stages of Aβ plaque development. In the cerebral cortex of homozygous transgenic animals (Tg++) without Aβ plaques (3m old), we observed subtle, dimorphic astrocytic morphological changes without evidence of a massive glial response. In Tg++ animals with incipient plaques (7m old), a gradient of astrocytic reactivity was observed in proximity to plaques, but reactivity was significant even in astrocytes distant from plaques when compared to WT animals. Microglial reactivity was also observed in Tg++ animals, suggesting a global alteration in the glial response at this age. Significant neuronal alterations were not observed at this age. In Tg++ animals with extensive extracellular Aβ deposits (13m old), astrocytic alterations were accompanied by a reduction in homeostatic gene expression (AQP4, GS) without evidence of pathological conversion to neurotoxic astrocytes (MAFG), alongside decreased neuronal survival. These findings indicate subtle early glial alterations before significant plaque deposition, followed by extensive reactive gliosis, but neuronal loss is a late event accompanied by impaired homeostatic capacity in astrocytes. This suggests that astroglial dysfunction is a final stage in AD, probably related to an exhausted astroglial phenotype. Grants: PUE, UBACYT, PIP-CONICET