Effect of age on the duration and extent of amyloid plaque reduction and microglial activation after injection of anti-Aβ antibody into the third ventricle of TgCRND8 mice

Abstract

We have previously shown that anti β-amyloid (Aβ) antibody injected into the third ventricle of mice is distributed throughout the brain within 24 hr and is completely washed out of brain within 36 hr after injection and that, in Tg2576 animals, a single injection of antibody reduces cerebral Aβ and restores presynaptic deficits 1 month after injection without producing hemorrhage or inflammation at an early plaque stage. Here we report the effects of a single ICV injection of anti-Aβ antibody on cerebral levels of immunoreactive Aβ and of microglial activation measured by immunoreactive interleukin-1β (IL-1β) at 1, 4, and 8 weeks after injections in TgCRND8 mice at two ages, 2 months (sparse plaques) and 8 months (abundant plaques). The data show that parenchymal amyloid accumulates before cerebral microvascular amyloid and that a single ICV injection reduces only parenchymal amyloid by about 70%, without affecting vascular amyloid, and reduces microglial activation by 46–60% at 1 week after injection. The reappearance of plaques after antibody injection takes 4–8 weeks, whereas plaque-associated focal microglial activation begins increasing between 1 and 4 weeks, suggesting that accumulation of nonfibrillar oligomeric Aβ may account for the earlier onset of microglial activation. No perivascular hemorrhage or inflammation was observed. These results suggest that periodic intraventricular administration of anti-Aβ is a potentially useful method for rapid reduction of both preexisting amyloid load and associated inflammation, providing a window of 4 weeks' duration for possible pharmacological cotreatment(s) to prevent de novo Aβ formation. This ICV method of passive immunization may be safer than active immunization, which has been known to produce encephalitis, or systemic passive immunization, which exposes amyloid-laden cerebral microvasculature to high levels of antibody in the blood and the potential of perivascular hemorrhages. © 2004 Wiley-Liss, Inc.