Human amyloid beta-induced neuroinflammation is an early event in neurodegeneration.
Using a human amyloid beta (Abeta) intracerebroventricular infusion mouse model of Alzheimer's disease-related injury, we previously demonstrated that systemic administration of a glial activation inhibitor could suppress neuroinflammation, prevent synaptic damage, and attenuate hippocampal-dependent behavioral deficits. We report that Abeta-induced neuroinflammation is an early event associated with onset and progression of pathophysiology, can be suppressed by the glial inhibitor over a range of intervention start times, and is amenable to suppression without inhibiting peripheral tissue inflammatory responses. Specifically, hippocampal neuroinflammation and neurodegeneration occur in close time proximity at 4-6 weeks after the start of infusion. Intraperitoneal administration of inhibitor for 2-week intervals starting at various times after initiation of Abeta infusion suppresses progression of pathophysiology. The glial inhibitor is a selective suppressor of neuroinflammation, in that it does not block peripheral tissue production of proinflammatory cytokines or markers of B- and T-cell activation after a systemic lipopolysaccharide challenge. These results support a causal link between neuroinflammation and neurodegeneration, have important implications for future therapeutic development, and provide insight into the relative time window for targeting neuroinflammation with positive neurological outcomes.
Craft
Jeffrey M
JM
Center for Drug Discovery and Chemical Biology, Northwestern University, Chicago, Illinois 60611, USA.
Watterson
D Martin
DM
Van Eldik
Linda J
LJ
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D015415:Biomarkers; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000473:pathology*; D007375:Interleukin-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000473:pathology*; D010525:Peripheral Nerves / Q000166:cytology / Q000473:pathology; D010523:Peripheral Nervous System Diseases / Q000473:pathology; D011724:Pyridazines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D007375:Interleukin-1; D008070:Lipopolysaccharides; C494131:MW01 070C; D011724:Pyridazines; D014409:Tumor Necrosis Factor-alpha