Tal Ganz, Israel
Hadassah - Hebrew University Medical Center NeurologyAuthor Of 1 Presentation
SYSTEMIC MICROBIAL AGENTS INDUCE NEURODEGENERATION IN ALZHEIMER'S DISEASE MICE
Abstract
Aims
Neurodegeneration is considered the consequence of misfolded proteins’ deposition. Little is known on external environmental effects on the neurodegenerative process. We studied whether systemic microbial pathogens may accelerate neurodegeneration in Alzheimer’s Disease (AD), and whether microglia play a central role in this process.
Methods
We examined cortical neuron density in transgenic 5xFAD and wild-type (wt) mice, that were housed in non-SPF versus SPF conditions, and in response to injection of bacterial lipopolysaccharide, a TLR4 agonist. Am580, a retinoic acid receptor α agonist, was delivered ICV by mini-osmotic pumps for regulation of Microglia. Microglial phenotype and functions were examined by ex vivo assays.
Results
In SPF conditions, 5xFAD mice exhibited marked AD pathology but no cortical neuronal loss at age 7 months, and mild loss at 12 months. Housing 5xFAD (but not wt) mice in a non-SPF environment caused accelerated neurodegeneration, occurring already at age 7 months. To model the effect of systemic pathogens, we injected LPS into wt and AD mice. 5xFAD mice exhibited increased vulnerability to LPS-induced neuronal loss compared to wt mice, mediated by CNS TLR4. Continuous ICV delivery of Am580 reduced neurotoxic iNOS+ brain microglia fraction, and protected from LPS-induced neurodegeneration. Am580 markedly attenuated iNOS expression, inhibited reactive oxygen species and nitric oxide production, increased TREM2 expression and phagocytic activity, while maintaining microglial capacity for immune (cytokine) response.
Conclusions
Systemic colonization with microbial pathogens and systemic infections cause neurodegeneration in brains displaying amyloid pathology. Microglial modulation protects the hyper-susceptible AD brain from microbial TLRs -induced neurodegeneration.