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.
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 (0.01 mg/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 kappa 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.
Arizona Research Laboratories Division of Neural Systems, Memory & Aging, University of Arizona, Tucson, AZ 85724, USA.
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D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D065100:CCR5 Receptor Antagonists; D004151:Dipeptides / Q000494:pharmacology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D007249:Inflammation; D008070:Lipopolysaccharides / Q000633:toxicity; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D018613:Microscopy, Confocal; D051381:Rats
D065100:CCR5 Receptor Antagonists; D004151:Dipeptides; D008070:Lipopolysaccharides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester