S14G-Humanin ameliorates Abeta25-35-induced behavioral deficits by reducing neuroinflammatory responses and apoptosis in mice.

Cerebral amyloid-beta protein (Abeta) deposition and associated neuroinflammation and apoptosis are increasingly recognized as an important component leading to cognitive impairment in Alzheimer's disease (AD). Humanin (HN) and its derivative, S14G-HN (HNG), are best known for their ability to suppress neuronal death induced by AD-related insults in vitro. Furthermore, limited in vivo studies show that HNG can ameliorate memory impairment induced by intracerebroventricular injection of anti-cholinergic drugs or Abeta25-35. However, the mechanism underlying the in vivo effect remains unclear. In this study, we sought to determine the effects of HNG on neuroinflammatory responses and apoptosis associated with behavioral deficits induced by Abeta25-35 in vivo. Our results indicate that intracerebroventricular injection of aggregated Abeta25-35 induced impairment of learning and memory, markedly elevated numbers of reactive astrocytes, activated microglia, and apoptotic cells, as well as remarkable increased levels of IL-6 and TNFalpha. Moreover, intraperitoneal HNG treatment ameliorated behavioral deficits, and reduced neuroinflammatory responses and apoptotic cells in the brain. Cumulatively, these finding demonstrate for the first time that HNG may have the potential for attenuating Abeta-induced cognitive deficits by reducing inflammatory responses and apoptosis in vivo, which may add to the novel evidence for anti-inflammatory and antiapoptosis properties of HNG in AD treatment.