Microglia Demonstrate Age-Dependent Interaction with Amyloid-beta Fibrils

Alzheimer's disease (AD) is an age-associated disease characterized by increased accumulation of extracellular amyloid-beta (A beta) plaques within the brain. Histological examination has also revealed profound microglial activation in diseased brains often in association with these fibrillar peptide aggregates. The paradoxical presence of increased, reactive microglia yet accumulating extracellular debris suggests that these cells may be phagocytically compromised during disease. Prior work has demonstrated that primary microglia from adult mice are unable to phagocytose fibrillar A beta(1-42) in vitro when compared to microglia cultured from early postnatal animals. These data suggest that microglia undergo an age-associated decrease in microglial ability to interact with A beta fibrils. In order to better define a temporal profile of microglia-A beta interaction, acutely isolated, rather than cultured, microglia from 2 month, 6 month, and postnatal day 0 C57BL/6 mice were compared. Postnatal day 0 microglia demonstrated a CD47 dependent ability to phagocytose A beta fibrils that was lost by 6 months. This corresponded with the ability of postnatal day 0 but not adult microglia to decrease A beta immunoreactive plaque load from AD sections in vitro. In spite of limited A beta uptake ability, adult microglia had functional phagocytic uptake of bacterial bioparticles and demonstrated the ability to adhere to both A beta plaques and in vitro fibrillized A beta. These data demonstrate a temporal profile of specifically A beta-microglia interaction with a critical developmental period at 6 months in which cells remain able to interact with A beta fibrils but lose their ability to phagocytose it.