Alzheimer disease （AD）, a progressive neurodegenerative disorder, is characterized by cognitive decline and the accumulation of senile plaques in the brain. Amyloid β protein （Aβ） in the plaques is thought to be responsible for the memory loss in AD patients. [Glyl4]- humanin （HNG）, a derivative of humanin （HN）, has much stronger neuroprotective effects than natural HN in vitro. However, clarification of the Aβ active center and the neuroprotective mechanism of HN still need in vivo evidence. The present study first compared the in vivo bio- logical effects of three Aβ fragments （1-42, 31-35, and 35-31） on spatial memory in rats, and investigated the neuroprotective effects and molecular mechanisms of HNG. The results showed that intrahippocampal injection of Aβ1-2 and Aβ1-35 almost equally impaired spatial learning and memory, but the reversed sequence Aβ1-31 did not have any effect; a high dose of Aβ1-35 （20 nmol） produced a more detrimental response than a low dose （2 nmol）; Aβ1-35 injection also disrupted gene and protein expression in the hippocampus, with up-regulation of caspase3 and down-regulation of STAT3; pretreatment with HNG not only protected spatial memory but also rescued STAT3 from Aβ-induced disruption; and the neuropro- tective effects of HNG were effectively counteracted by genistein, a specific tyrosine kinase inhibitor. These results clearly show that sequence 31-35 in AI5 is the shortest active center responsible for the neurotoxicity of A[3 from molecule to behavior; and HNG protects spatial learning and memory in rats against Aβ-indnced insults; and prob- ably involves the activation of tyrosine kinases and sub- sequent beneficial modulation of STAT3 and caspase3.
Li YuanXiao-Jie LiuWei-Na HanQing-Shan LiZhao-Jun WangMei-Na WuWei YangJin-Shun Qi
