Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice.

Inflammation has been argued to play a fundamental role in the pathogenesis of Alzheimer's disease. Mice transgenic for mutant human amyloid precursor protein (APP) develop progressive amyloid deposition, gliosis, and cognitive impairment. Paradoxically, intracranial administration of lipopolysaccharide (LPS) to promote neuroinflammation results in a reduction in amyloid-beta peptide (Abeta) burden concurrent with the inflammatory response. To determine whether microglia mediate Abeta clearance after LPS, we used dexamethasone to inhibit the microglial response. Amyloid precursor protein mice were injected intrahippocampally with either LPS or saline and were allowed to survive for 7 days with or without dexamethasone cotreatment. Brain tissue was then analyzed by immunohistochemistry. Hippocampal Abeta burden was reduced 7 days after LPS injection, and this was prevented by cotreatment with dexamethasone. Markers of microglial activation [CD45, complement receptor 3 (CR3), and macrosialin (CD68)] were increased by LPS, and these increases were attenuated by dexamethasone. Dexamethasone failed to block LPS-induced increases in all microglial markers, and Fcgamma receptors II/III and scavenger receptor A were increased by LPS but were unaffected by dexamethasone cotreatment. These results indicate a complex response by microglia to acute LPS treatment, with only some responses sensitive to steroidal anti-inflammatory drug treatment. Nonetheless, microglial activation was necessary to remove Abeta in this model of neuroinflammation.

Diverse microglial responses after intrahippocampal administration of lipopolysaccharide.

Inflammation has been argued to play a primary role in the pathogenesis of Alzheimer's disease by contributing to the development of neuropathology and clinical symptoms. However, the mechanisms underlying these effects remain obscure. Lipopolysaccharide (LPS) activates the innate immune response and triggers gliosis when injected into the central nervous system. In the studies described in the present work, we evaluated the time course of microgliosis after a single intrahippocampal injection of LPS. Mice were injected bilaterally with 4 mug of LPS. Post-injection survival times were 1, 6, and 24 h, as well as 3, 7, 14, and 28 days. Protein and RNA analyses were performed for inflammatory markers. Significant elevations of cluster differentiation marker CD45, glial fibrillary acidic protein (GFAP), scavenger receptor A (SRA), and Fcgamma receptor mRNA were seen after 24 h. Immunohistochemistry revealed a complex pattern of protein expression by microglia, as well as changes in cell morphologies. RNA and protein for Fcgamma receptor and SRA were transiently elevated, peaked at 3 days, and returned to basal levels after 1 week. In contrast, microglia remained significantly activated through the 28-day time point, as determined by CD45 and complement receptor 3 levels. These findings indicate a multivariate response to LPS, and evaluation of microglial phenotypes may lead to a better understanding of neuroinflammatory diseases.

Time-dependent reduction in Abeta levels after intracranial LPS administration in APP transgenic mice.

Inflammation has been argued to play a primary role in the pathogenesis of Alzheimer's disease (AD). Lipopolysaccharide (LPS) activates the innate immune system, triggering gliosis and inflammation when injected in the central nervous system. In studies described here, APP transgenic mice were injected intrahippocampally with 4 or 10 microg of LPS and evaluated 1, 3, 7, 14, or 28 days later. Abeta load was significantly reduced at 3, 7, and 14 days but surprisingly returned near baseline 28 days after the injection. No effects of LPS on congophilic amyloid deposits could be detected. LPS also activated both microglia and astrocytes in a time-dependent manner. The GFAP astrocyte reaction and the Fcgamma receptor microglial reaction peaked at 7 days after LPS injection, returning to baseline by 2 weeks postinjection. When stained for CD45, microglial activation was detected at all time points, although the morphology of these cells transitioned from an ameboid to a ramified and bushy appearance between 7 and 14 days postinjection. These results indicate that activation of brain glia can rapidly and transiently clear diffuse Abeta deposits but has no effect on compacted fibrillar amyloid.