S14G-Humanin improves cognitive deficits and reduces amyloid pathology in the middle-aged APPswe/PS1dE9 mice

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by clinical cognitive decline and pathological deposition of amyloid-beta protein (A beta) in the brain. So far, there has been no causative therapy for this devastating disease. S14G-Humanin (HNG), a synthetic derivative of Humanin (HN), has been shown to have strong neuroprotective ability against AD-related insults in vitro and prevent cognitive impairments in A beta-infused animal models. In addition, a recent study has reported a beneficial effect of intranasal HNC treatment on memory deficit and A beta accumulation in triple transgenic (3xTg-AD) mice at the early plaque-bearing stage. However, whether HNG treatment has the disease-modifying efficacy on AD with pre-existing well-established amyloid plaque pathology remains unclear. In this study, vie employed 9-month-old APPswe/PS1dE9 mice with pre-existing robust amyloid plaque pathology to investigate the effects of chronic HNG treatment on the progression of cognitive dysfunction and A beta-associated neuropathology. We found that vehicle-treated APPswe/PS1dE9 mice showed impaired spatial learning and memory compared with vehicle- and HNG-treated wild-type mice, while intraperitoneal HNG treatment for 3 months significantly improved spatial learning and memory deficits in APPswe/PS1dE9 mice compared with vehicle control treatment. Coincidental with this, HNG treatment significantly reduced cerebral A beta plaque deposition, insoluble A beta levels, and neuroinflammatory responses in APPswe/PS1dE9 mice compared with control treatment. Cumulatively, these findings demonstrate that chronic administration of HNG is able to attenuate cognitive deficits and reduce A beta loads as well as neuroinflammation in the middle-aged APPswe/PS1dE9 mice even with pre-existing substantial A beta neuropathology, indicating that HNG has potential as a pharmatotherapeutic intervention in the development of cognitive deficits and neuropathology seen in the cases of established AD. (C) 2011 Elsevier Inc. All rights reserved.