Matthew Inlay, United States of America
Univerity of California, Irvine Department of Neurobiology & BehaviorAuthor Of 1 Presentation
A GENETIC ABSENCE OF MICROGLIA PROMOTES CEREBROVASCULAR PATHOLOGY AND PREMATURE MORTALITY IN 5XFAD MICE WHICH CAN BE PARTIALLY RESCUED BY MICROGLIAL TRANSPLANTATION
Abstract
Aims
Microglia are strongly implicated in the development and progression of Alzheimer’s disease (AD). To further understand how microglia impact AD pathology, we crossed 5xfAD mice with ‘FIRE’ mice, a novel model that genetically lacks microglia. Compared to other genetic or pharmacological methods, this new approach allows one to understand how a consistent absence of microglia impacts disease progression. The resulting empty microglia niche also enables the robust repopulation of microglia from genetically modified donors.
Methods
‘FIRE’ mice harboring a deletion in the fms-intronic regulatory element of CSF1R and lack microglia were backcrossed with 5xfAD mice. Immunohistochemical and biochemical analysis was used to determine the impact of microglial absence on disease pathology. In addition, transplantation of wild-type donor microglia was performed to determine the impact of microglial replacement on these endpoints.
Results
Pharmacological depletion of microglial has not been reported to effect AD mouse mortality. In contrast, we found that FIREKO-5xFAD mice that genetically lack microglia, exhibit a significantly shortened lifespan, with few mice reaching 6 months of age. Interestingly, this increased mortality is accompanied by a significant reduction in parenchymal beta-amyloid plaques, but a dramatic increase in cerebral amyloid angiopathy (CAA) and other signs of blood brain barrier (BBB) pathology and disruption. Remarkably, transplantation of Wild Type donor microglia rescues many, but not all, of these changes.
Conclusions
The FIREKO-5xFAD model provides a novel platform to determine how microglia influence the relationship between plaque formation and blood vessel pathology and the impact of varying microglial donor cells on these outcomes.