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.

Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice.

Systemic administration of anti-amyloid-beta (Abeta) antibodies results in reduced parenchymal amyloid but increased vascular amyloid and microhemorrhage in amyloid precursor protein (APP) transgenic mice. Here, we evaluate the effects of reducing effector interactions of the antibody via deglycosylation. Mice aged 20 months were treated weekly for 4 months and tested behaviorally before they were killed. APP transgenic mice receiving either anti-Abeta (2H6) or deglycosylated anti-Abeta (de-2H6) showed significant improvement in radial arm water maze performance compared with mice receiving a control antibody. Both groups receiving anti-Abeta antibodies showed significant reductions in total Abeta immunochemistry and Congo red. Significantly fewer vascular amyloid deposits and microhemorrhages were observed in mice administered the de-2H6 antibody compared with those receiving unmodified 2H6 antibody. Deglycosylated anti-Abeta antibodies may be preferable to unmodified IgG because they retain the cognition-enhancing and amyloid-reducing properties of anti-Abeta immunotherapy, while greatly attenuating the increased vascular amyloid deposition and microhemorrhage observed with unmodified IgG.