ALTERED ARC IMMEDIATE EARLY GENE PROTEIN EXPRESSION DURING CHRONIC BRAIN INFLAMMATION IN THE HIPPOCAMPUS

S. Rosi¹*; V. Ramirez-Amaya¹; C.A. Barnes¹; B. Hauss-Wegrzyniak¹; P.F. Worley²; G.L. Wenk¹

1. Div of Neural Systems, Memory & Aging, Univ of Arizona, Tucson, AZ, USA
2. Neurosci, Johns Hopkins, Baltimore, MD, USA

The hippocampus plays a central role in learning and memory and shows extensive neuropathological changes in Alzheimer s disease (AD). Widespread neuroinflammation is also seen in AD and can be modeled in rats by chronic infusion of lipopolysaccharide (LPS) into the 4th ventricle. Arc is an immediate early gene that can be induced in hippocampal neurons by spatial exploration and is thought to be involved in memory consolidation. We studied the expression of Arc protein after spatial exploration in rats that received either LPS or aCSF infusions. Our prediction was that chronic neuroinflammation would alter behavioral induced Arc expression in the hippocampus. LPS or aCSF was chronically infused for 28 days and immediately thereafter the animals underwent spatial exploration for 5 min; 90 min later, the animals were sacrificed by decapitation and their brains removed and frozen. Fluorescence immunolabeling identified both Arc protein as a measure of cell activity and OX-6-positive activated microglia as a measure of neuroinflammation. Surprisingly, LPS induced neuroinflammation increased the number of Arc protein positive cells in the dentate gyrus. We have previously shown that LPS-induced neuroinflammation in rats reproduces many of the behavioral, neurochemical, electrophysiological and neuropathological changes associated with AD. Therefore, our results are consistent with the hypothesis that chronic neuroinflammation associated with AD might alter hippocampal activity patterns, which result in an increase of Arc expression in the dentate gyrus and could contribute significantly to the cognitive deficits observed in this neurodegenerative disease.

Support Contributed By: NIH, AG10546, and the Alzheimer’s Association, IIRG-01-2654 (GLW) and AG09219 (CAB) and the Human Frontiers Science Program LT00112-2002-C (VRA)