Melatonin protects against amyloid-β-induced impairments of hippocampal LTP and spatial learning in rats.

Alzheimer's disease (AD), the most prevalent neurodegenerative disease in the elderly, leads to progressive loss of memory and cognitive deficits. Amyloid-β protein (Aβ) in the brain is thought to be the main cause of memory loss in AD. Melatonin, an indole hormone secreted by the pineal gland, has been reported to produce neuroprotective effects. We examined whether melatonin could protect Aβ-induced impairments of hippocampal synaptic plasticity, neuronal cooperative activity, and learning and memory. Rats received bilateral intrahippocampal injection of Aβ1-42 or Aβ31-35 followed by intraperitoneal application of melatonin for 10 days, and the effects of chronic melatonin treatment on in vivo hippocampal long-term potentiation (LTP) and theta rhythm and Morris water maze performance were examined. We showed that intrahippocampal injection of Aβ1-42 or Aβ31-35 impaired hippocampal LTP in vivo, while chronic melatonin treatment reversed Aβ1-42- or Aβ31-35-induced impairments in LTP induction. Intrahippocampal injection of Aβ31-35 impaired spatial learning and decreased the power of theta rhythm in the CA1 region induced by tail pinch, and these synaptic, circuit, and learning deficits were rescued by chronic melatonin treatment. These results provide evidence for the neuroprotective action of melatonin against Aβ insults and suggest a strategy for alleviating cognition deficits of AD.

Liu XJ ，Yuan L ，Yang D ，Han WN ，Li QS ，Yang W ，Liu QS ，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 ... -  《-》

Val8-glucagon-like peptide-1 protects against Aβ1-40-induced impairment of hippocampal late-phase long-term potentiation and spatial learning in rats.

Amyloid β protein (Aβ) is considered to be partly responsible for the impairment of learning and memory in Alzheimer disease (AD). In addition, it has been found recently that type 2 diabetes mellitus (T2DM) is a risk factor for developing AD. One promising treatment for AD is using analogues for the insulin-release facilitating gut hormone glucagon-like peptide-1 (GLP-1) that has been developed as a T2DM therapy. GLP-1 has been shown to have neuroprotective properties. However, if GLP-1 can protect the late phase-long term potentiation (L-LTP) and related cognitive function against Aβ-induced impairment it is still an open question. To further characterize the neuroprotective function of GLP-1 in the brain, we investigated the effects of i.c.v. injected Val(8)-GLP-1(7-36) on the Aβ fragment-induced impairment of in vivo hippocampal L-LTP and spatial learning and memory in rats. The results showed that (1) Aβ1-40 (5 nmol) injection did not affect the baseline field excitatory postsynaptic potentials (fEPSPs), but significantly suppressed multiple high frequency stimulation (HFS)-induced L-LTP in hippocampal CA1 region; (2) Val(8)-GLP-1(7-36) (0.05 pmol) administration alone did not affect the baseline synaptic transmission and the maintenance of L-LTP; (3) pretreatment with Val(8)-GLP-1(7-36) (0.05 pmol) effectively prevented Aβ1-40-induced deficit of L-LTP; (4) i.c.v. injection of 5 nmol Aβ1-40 resulted in a significant decline learning a spatial Morris water maze (MWM) test; (5) Val(8)-GLP-1(7-36) (0.05 pmol) administration alone did not affect spatial learning in this task, while pretreatment with Val(8)-GLP-1(7-36) effectively reversed the impairment of spatial learning and memory induced by Aβ1-40. At the same time, the swim speeds and escape latencies of rats among all groups in the visible platform tests did not show any difference. These results suggest that increase of GLP-1 signalling in the brain may be a promising strategy to ameliorate the degenerative processes observed in AD.

Wang XH ，Li L ，Hölscher C ，Pan YF ，Chen XR ，Qi JS ... -  《-》

Davunetide improves spatial learning and memory in Alzheimer's disease-associated rats.

Memory loss and cognition decline are the main clinical manifestations of Alzheimer's disease (AD). Amyloid β protein (Aβ) aggregated in the brain is one of the key pathological characteristics of AD and responsible for the deficits in learning and memory. It is reported that davunetide, an octapeptide derived from activity-dependent neuroprotective protein (ADNP), inhibited Aβ aggregation and Aβ-induced neurotoxicity. To further characterize the neuroprotective roles of davunetide and its possible mechanism, the present study investigated the effects of davunetide on Aβ1-42-induced impairments in spatial memory, synaptic plasticity and hippocampal AKT level. In Morris water maze (MWM) test, bilateral intrahippocampal injection of Aβ1-42 significantly increased escape latency and decreased target quadrant swimming time of rats, while three weeks of intranasal application of davunetide reversed the Aβ1-42-induced learning deficits and memory loss in a dose-dependent manner. In vivo field potentiation recording showed that Aβ1-42 suppressed long-term potentiation (LTP) of excitatory postsynaptic potential (fEPSP) in the hippocampal CA1 region of rats, while davunetide effectively blocked the suppression of LTP, without affecting paired-pulse facilitation (PPF). Western blotting experiments showed a significant decrease in the level of hippocampal p-AKT (Ser473), not total AKT, in Aβ1-42 only group, which was mostly antagonized by davunetide treatment. These findings demonstrate that davunetide, probably by enhancing PI3K/AKT pathway, plays an important positive role in attenuating Aβ1-42-induced impairments in spatial memory and synaptic plasticity, suggesting that davunetide could be an effective therapeutic candidate for the prevention and treatment of neurodegenerative disease such as AD.

Zhang J ，Wei SY ，Yuan L ，Kong LL ，Zhang SX ，Wang ZJ ，Wu MN ，Qi JS ... -  《-》

Leptin attenuates the detrimental effects of β-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats.

β-Amyloid (Aβ) is the main component of amyloid plaques developed in the brain of patients with Alzheimer's disease (AD). The increasing burden of Aβ in the cortex and hippocampus is closely correlated with memory loss and cognition deficits in AD. Recently, leptin, a 16kD peptide derived mainly from white adipocyte tissue, has been appreciated for its neuroprotective function, although less is known about the effects of leptin on spatial memory and synaptic plasticity. The present study investigated the neuroprotective effects of leptin against Aβ-induced deficits in spatial memory and in vivo hippocampal late-phase long-term potentiation (L-LTP) in rats. Y maze spontaneous alternation was used to assess short term working memory, and the Morris water maze task was used to assess long term reference memory. Hippocampal field potential recordings were performed to observe changes in L-LTP. We found that chronically intracerebroventricular injection of leptin (1μg) effectively alleviated Aβ1-42 (20μg)-induced spatial memory impairments of Y maze spontaneous alternation and Morris water maze. In addition, chronic administration of leptin also reversed Aβ1-42-induced suppression of in vivo hippocampal L-LTP in rats. Together, these results suggest that chronic leptin treatments reversed Aβ-induced deficits in learning and memory and the maintenance of L-LTP.

Tong JQ ，Zhang J ，Hao M ，Yang J ，Han YF ，Liu XJ ，Shi H ，Wu MN ，Liu QS ，Qi JS ... -  《-》