Colivelin ameliorates amyloid β peptide-induced impairments in spatial memory, synaptic plasticity, and calcium homeostasis in rats.

Amyloid β peptide (Aβ) has been thought to be neurotoxic and responsible for the impairment of learning and memory in Alzheimer's disease (AD). Humanin (HN), a 24 amino acid polypeptide first identified from the unaffected occipital lobe of an AD patient, is believed to be neuroprotective against the AD-related neurotoxicity. In this study, we investigated the neuroprotective effects of Colivelin (CLN), a novel HN derivative, against Aβ by using behavioral test, in vivo electrophysiological recording, and intracellular calcium imaging. Our results showed that intrahippocampal injection of CLN (0.2 nmol) effectively prevented Aβ25-35 (4 nmol)-induced deficits in spatial learning and memory of rats in Morris water maze test; the suppression of in vivo hippocampal long term potentiation (LTP) by Aβ25-35 was nearly completely prevented by CLN; in addition, CLN pretreatment also effectively inhibited Aβ25-35-induced calcium overload in primary cultured hippocampal neurons. These results indicate that CLN has significant neuroprotective properties against Aβ, and CLN may holds great promise for the treatment and prevention of AD.

Wu MN ，Zhou LW ，Wang ZJ ，Han WN ，Zhang J ，Liu XJ ，Tong JQ ，Qi JS ... -  《-》

Colivelin Ameliorates Impairments in Cognitive Behaviors and Synaptic Plasticity in APP/PS1 Transgenic Mice.

Wu M ，Shi H ，He Y ，Yuan L ，Qu X ，Zhang J ，Wang Z ，Cai H ，Qi J ... -  《-》

Wnt-5a prevents Aβ-induced deficits in long-term potentiation and spatial memory in rats.

Although the neurotoxicity of amyloid β (Aβ) protein in Alzheimer's disease (AD) has been reported widely, the exact molecular mechanism underlying the Aβ-induced synaptic dysfunction and memory impairment remains largely unclear. Growing evidence indicates that wingless-type (Wnt) signaling plays an important role in neuronal development, synapse formation and synaptic plasticity. In the present study, we investigated the neuroprotective action of Wnt-5a against the synaptic damage and memory deficit induced by Aβ25-35 by using in vivo electrophysiological recording and Morris water maze (MWM) test. We found that intracerebroventricular (i.c.v.) injection of Aβ25-35 alone did not affect the baseline field excitatory postsynaptic potentials (fEPSPs) and the paired-pulse facilitation (PPF) in the hippocampal CA1 region of rats, but significantly suppressed high frequency stimulation (HFS) induced long-term potentiation (LTP); pretreatment with Wnt-5a prevented the Aβ25-35-induced suppression of hippocampal LTP in a dose-dependent manner; soluble Frizzled-related protein (sFRP), a specific Wnt antagonist, effectively attenuated the protective effects of Wnt-5a. In MWM test, Aβ25-35 alone significantly disrupted spatial learning and memory ability of rats, while pretreatment with Wnt-5a effectively prevented the impairments induced by Aβ25-35. These results in the present study demonstrated for the first time the neuroprotective effects of Wnt-5a against Aβ-induced in vivo synaptic plasticity impairment and memory disorder, suggesting that Wnt signaling pathway is one of the important targets of Aβ neurotoxicity and Wnt-5a might be used as one of the putative candidates for the therapeutic intervention of AD.

Zhang GL ，Zhang J ，Li SF ，Lei L ，Xie HY ，Deng F ，Feng JC ，Qi JS ... -  《-》

Lixisenatide rescues spatial memory and synaptic plasticity from amyloid β protein-induced impairments in rats.

Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by cognitive impairment, but effective strategies against AD are currently not available. Interestingly, glucagon-like peptide-1 (GLP-1) used in type 2 diabetes mellitus (T2DM) has shown neuroprotective effects in preclinical studies of AD. Lixisenatide, an effective GLP-1 receptor (GLP-1R) agonist with much longer half life than GLP-1, has been licensed in the EU as a treatment for T2DM. However, the neuroprotective effects of lixisenatide in the brain remain to be clarified. In the present study, we report for the first time the effects of lixisenatide on the amyloid β (Aβ) protein-induced impairments in spatial learning and memory of rats, and investigated its electrophysiological and molecular mechanisms. We found that: (1) bilateral intrahippocampal injection of Aβ25-35 resulted in a significant decline in spatial learning and memory of rats, as well as a suppression of in vivo hippocampal long-term potentiation (LTP); (2) lixisenatide treatment effectively prevented the Aβ25-35-induced impairments; (3) lixisenatide inhibited the Aβ25-35 injection-induced activation of glycogen synthase kinase 3β (GSK3β), with a significant increase in the phosphorylation of ser9 and a significant decrease in the phosphorylation of Y216. These results indicate that lixisenatide, by affecting the PI3K-Akt-GSK3β pathway, can prevent Aβ-related impairments in synaptic plasticity and spatial memory of rats, suggesting that lixisenatide may be a novel and effective treatment for AD.

Cai HY ，Hölscher C ，Yue XH ，Zhang SX ，Wang XH ，Qiao F ，Yang W ，Qi JS ... -  《-》

The neuroprotection of Rattin against amyloid β peptide in spatial memory and synaptic plasticity of rats.

Rattin, a specific derivative of humanin in rats, shares the ability with HN to protect neurons against amyloid β (Aβ) peptide-induced cellular toxicity. However, it is still unclear whether Rattin can protect against Aβ-induced deficits in cognition and synaptic plasticity in rats. In the present study, we observed the effects of Rattin and Aβ31-35 on the spatial reference memory and in vivo hippocampal Long-term potentiation of rats by using Morris water maze test and hippocampal field potential recording. Furthermore, the probable molecular mechanism underlying the neuroprotective roles of Rattin was investigated. We showed that intra-hippocampal injection of Rattin effectively prevented the Aβ31-35-induced spatial memory deficits and hippocampal LTP suppression in rats; the Aβ31-35-induced activation of Caspase-3 and inhibition of STAT3 in the hippocampus were also prevented by Rattin treatment. These findings indicate that Rattin treatment can protect spatial memory and synaptic plasticity of rats against Aβ31-35-induced impairments, and the underlying protective mechanism of Rattin may be involved in STAT3 and Caspases-3 pathways. Therefore, application of Rattin or activation of its signaling pathways in the brain might be beneficial to the prevention of Aβ-related cognitive deficits.

Wang ZJ ，Han WN ，Yang GZ ，Yuan L ，Liu XJ ，Li QS ，Qi JS ... -  《-》