Elsevier

Neuroscience

Volume 134, Issue 2, 2005, Pages 671-676
Neuroscience

Systems neuroscience
Chemokine receptor 5 antagonist d-Ala-peptide T-amide reduces microglia and astrocyte activation within the hippocampus in a neuroinflammatory rat model of Alzheimer's disease

https://doi.org/10.1016/j.neuroscience.2005.04.029Get rights and content

Abstract

Chronic neuroinflammation plays a prominent role in the progression of Alzheimer's disease. Reactive microglia and astrocytes are observed within the hippocampus during the early stages of the disease. Epidemiological findings suggest that anti-inflammatory therapies may slow the onset of Alzheimer's disease. Chemokine receptor 5 (CCR5) up-regulation may influence the recruitment and accumulation of glia near senile plaques; activated microglia express CCR5 and reactive astrocytes express chemokines. We have previously shown that neuroinflammation induced by chronic infusion of lipopolysaccharide into the 4th ventricle reproduces many of the behavioral, neurochemical, electrophysiological and neuropathological changes associated with Alzheimer's disease. The current study investigated the ability of d-Ala-peptide T-amide (DAPTA), a chemokine receptor 5 chemokine receptor antagonist of monocyte chemotaxis, to influence the consequences of chronic infusion of lipopolysaccharide. DAPTA (0.01mg/kg, s.c., for 14 days) dramatically reduced the number of activated microglia and astrocytes, as compared with lipopolysaccharide-infused rats treated with vehicle. DAPTA treatment also reduced the number of immunoreactive cells expressing nuclear factor κ binding protein, a prominent component of the proinflammatory cytokine signaling pathway. The present study suggests that DAPTA and other CCR5 antagonists may attenuate critical aspects of the neuroinflammation associated with Alzheimer's disease.

Section snippets

Subjects

Eighteen male, three month old, F-344 (Harlan Sprague–Dawley, Indianapolis, IN, USA) were assigned to three groups: 1) artificial cerebrospinal fluid (aCSF)-infused (n=6); 2) LPS-infused, vehicle-treated (n=6); 3) LPS-infused, DAPTA-treated (0.01mg/kg/day, s.c, n=6). LPS (1.0μg/μl) or was chronically infused (0.25μl/h for 14 days) through a cannula implanted into the 4th ventricle of the brain that was attached to an osmotic minipump as previously described (Hauss-Wegrzyniak et al., 1998,

Results

Chronic infusion of LPS into the 4th ventricle of young rats for 2 weeks was well tolerated by all rats. Initially after surgery, all LPS-infused rats lost a few grams of weight. Within a few days, however, most rats had regained weight and continued to gain weight normally for the duration of the study (Rosi et al., 2005).

Discussion

Chronic infusion of LPS into the 4th ventricle produced an extensive inflammatory reaction throughout the brain, particularly within the hippocampus and temporal lobe regions. The inflammatory response was characterized by a significant increase in the number of reactive microglial cells, a marked hypertrophy of numerous astrocytes and an elevation in the NFkB staining. The effects of LPS infusion upon microglial and astrocyte activation were consistent with our previous reports (

Acknowledgments

Supported by the U.S. Public Health Service, Contract grant number AG10546 and the Alzheimer's Association, IIRG-01-2654 to G.L.W.

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