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PROTECTIVE EFFECTS OF A PHOSPHATIDYLCHOLINE-ENRICHED DIET IN LIPOPOLYSACCHARIDE-INDUCED EXPERIMENTAL NEUROINFLAMMATION IN THE RAT

SHOCK (2011)

期刊

SHOCK

卷 36, 期 5, 页码 458-465

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LIPPINCOTT WILLIAMS & WILKINS

DOI: 10.1097/SHK.0b013e31822f36b0

关键词

Hippocampus; neurogenesis; microglia; neuroprogenitors; TNF-alpha

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Critical Care Medicine Hematology Surgery Peripheral Vascular Disease

资金

Hungarian Science Research Fund OTKA [K75161, TAMOP-4.2.2-08/1/2008-0013, TAMOP 4.2.1/B-09/1]

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摘要

Our goal was to characterize the neuroprotective properties of orally administered phosphatidylcholine (PC) in a rodent model of systemic inflammation. Sprague-Dawley rats were killed at 3 h, 1 day, 3 days, or 7 days after i.p. administration of lipopolysaccharide (LPS) to determine the plasma levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 cytokines. The control group and one group of LPS-treated animals were nourished with standard laboratory chow, whereas another LPS-treated group received a special diet enriched with 1% PC for 5 days before the administration of LPS and thereafter during the 7-day observation period. Immunohistochemistry was performed to visualize the bromodeoxyuridine and doublecortin-positive neuroprogenitor cells and Iba1-positive microglia in the hippocampus, whereas the degree of mucosal damage was evaluated on ileal and colon biopsy samples after hematoxylin-eosin staining. The activities of proinflammatory myeloperoxidase and xanthine-oxidoreductase and the tissue nitrite/nitrate (NO(x)) level were additionally determined, and the cognitive functions were monitored via Morris water maze testing. The inflammatory challenge transiently increased the hippocampal NO(x) level and led to microglia accumulation and decreased neurogenesis. The intestinal damage, mucosal myeloperoxidase, xanthine-oxidoreductase, and NO(x) changes were less pronounced, and long-lasting behavioral alterations were not observed. Phosphatidylcholine pretreatment reduced the plasma TNF-alpha and hippocampal NO(x) changes and prevented the decreased neurogenesis. These data demonstrated the relative susceptibility of the brain to the consequences of transient peripheral inflammatory stimuli. Phosphatidylcholine supplementation did not reduce the overall extent of peripheral inflammatory activation, but efficiently counteracted the disturbed hippocampal neurogenesis by lowering circulating TNF-alpha concentrations.

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Early death in a mouse model of Alzheimer's disease exacerbated by microglial loss of TAM receptor signaling

Youtong Huang, Greg Lemke

Summary: Recurrent seizures, which may contribute to the pathogenesis and cognitive decline of Alzheimer's disease, are common in early-stage AD and mouse models that overproduce amyloid beta. In a study of the APP/PS1 mouse model, it was found that the mutation of TAM receptor tyrosine kinase (RTK) Mer or its ligand Gas6 significantly increased the risk of early death, which was tied to violent seizures originating in the dentate gyrus of the hippocampus. TAM-deficient mice showed increased newborn DG neurons and excitatory synapses, coinciding with premature death and adult neurogenesis. In contrast, the incidence of lethal seizures was strongly anticorrelated with the deposition of dense-core amyloid plaques. These findings suggest that TAM-mediated phagocytosis influences synaptic connectivity in the hippocampus and that seizure-inducing amyloid beta polymers are present before the formation of dense-core plaques.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2022)