Zhao-Jun Wang

Val8-GLP-1 remodels synaptic activity and intracellular calcium homeostasis impaired by amyloid β peptide in rats

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimers disease (AD) in the elderly. Glucagon‐like peptide‐1 (GLP‐1), a modulator in T2DM therapy, has been shown to have neuroprotective properties. However, the native GLP‐1 can be rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV); the neuroprotective mechanism of GLP‐1 in the central nervous system is still an open question, and whether GLP‐1 can prevent amyloid β (Aβ)‐induced synaptic dysfunction and calcium disorder is still unclear. The present study, by using patch clamp and calcium imaging techniques, investigated the effects of Val8‐GLP‐1(7–36), a GLP‐1 analogue with profound resistance to DPP IV, on the excitatory and inhibitory synaptic transmission and intracellular calcium concentration ([Ca2+]i) in the absence or presence of Aβ1–40. The results showed that 1) Aβ1–40 significantly reduced the frequency of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) in CA1 pyramidal neurons of rat brain slices; 2) Val8‐GLP‐1(7–36) did not affect the activity of miniature postsynaptic currents but effectively protected against the Aβ1–40‐induced decrease in mEPSC and mIPSC frequency; 3) Aβ1–40 significantly increased [Ca2+]i in primary neuronal cultures; and 4) Val8‐GLP‐1(7–36) alone did not change the intracellular calcium level but prevented Aβ1–40‐induced persistent elevation of [Ca2+]i. These findings demonstrate for the first time that central application of Val8‐GLP‐1(7–36) could protect against Aβ‐induced synaptic dysfunction and intracellular calcium overloading, suggesting that the neuroprotection of GLP‐1 may be involved in the remodeling of synaptic activity and intracellular calcium homeostasis in the brain.

Lixisenatide attenuates the detrimental effects of amyloid β protein on spatial working memory and hippocampal neurons in rats

&NA; Type 2 diabetes mellitus(T2DM) is a risk factor of Alzheimers disease (AD), which is most likely linked to impairments of insulin signaling in the brain. Hence, drugs enhancing insulin signaling may have therapeutic potential for AD. Lixisenatide, a novel long‐lasting glucagon‐like peptide 1 (GLP‐1) analogue, facilitates insulin signaling and has neuroprotective properties. We previously reported the protective effects of lixisenatide on memory formation and synaptic plasticity. Here, we describe additional key neuroprotective properties of lixisenatide and its possible molecular and cellular mechanisms against AD‐related impairments in rats. The results show that lixisenatide effectively alleviated amyloid &bgr; protein (A&bgr;) 25‐35‐induced working memory impairment, reversed A&bgr;25‐35‐triggered cytotoxicity on hippocampal cell cultures, and prevented against A&bgr;25‐35‐induced suppression of the Akt‐MEK1/2 signaling pathway. Lixisenatide also reduced the A&bgr;25‐35 acute application induced intracellular calcium overload, which was abolished by U0126, a specific MEK1/2 inhibitor. These results further confirmed the neuroprotective and cytoprotective action of lixisenatide against A&bgr;‐induced impairments, suggesting that the protective effects of lixisenatide may involve the activation of the Akt‐MEK1/2 signaling pathway and the regulation of intracellular calcium homeostasis. HighlightsLixisenatide, a drug already on the market to treat diabetes, shows neuroprotective effects.In a rat model of Alzheimers disease, lixisenatide prevented memory loss induced by amyloid ICV injection.Intracellular calcium levels were normalised by the drug.The protective effect was blocked by a MEK1/2 kinase inhibitor.

High‐intensity treadmill running impairs cognitive behavior and hippocampal synaptic plasticity of rats via activation of inflammatory response

Although appropriate exercise is beneficial for enhancing brain functions, high‐intensity exercise (HIE)‐induced cognitive dysfunction is causing more and more concerns nowadays. In the present study, we observed the effects of high‐intensity treadmill running on the spatial learning of the adult Sprague Dawley male rats in Y‐maze (n = 16 per group), and investigated its possible electrophysiological and molecular mechanisms by examining in vivo hippocampal long‐term potentiation (LTP), central inflammatory responses, and JNK/p38/ERK signal pathway. The Y‐maze active avoidance test showed that high‐intensity treadmill running impaired spatial learning ability of rats, with increased error times and prolonged training time in recognizing safety condition. Associated with the cognitive dysfunction, the induction and maintenance of hippocampal LTP were also impaired by the HIE. Furthermore, accompanied by elevated levels of inflammatory factors IL‐1β, TNF‐α, and iNOS, overactivation of microglia and astrocytes was also found in the CA1 region of hippocampus in the excessive exercise group, indicating an inflammatory response induced by HIE. In addition, Western blot assay showed that the phosphorylation of JNK/p38/ERK proteins was enhanced in the exercise group. These results suggest that exercise stress–induced neuronal inflammatory responses in the hippocampus are associated with HIE‐induced cognitive deficits, which may be involved in the upregulation of the JNK/p38/ERK pathway.

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 Alzheimers 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.

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.

Steroid sulfatase inhibitor DU-14 protects spatial memory and synaptic plasticity from disruption by amyloid β protein in male rats.

Alzheimers disease (AD) is an age-related mental disorder characterized by progressive loss of memory and multiple cognitive impairments. The overproduction and aggregation of Amyloid β protein (Aβ) in the brain, especially in the hippocampus, are closely involved in the memory loss in the patients with AD. Accumulating evidence indicates that the Aβ-induced imbalance of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) in the brain plays an important role in the AD pathogenesis and progression. The level of DHEA is elevated, while DHEAS is dramatically decreased in the AD brain. The present study tried to restore the balance between DHEA and DHEAS by using a non-steroidal sulfatase inhibitor DU-14, which increases endogenous DHEAS through preventing DHEAS converted back into DHEA. We found that: (1) DU-14 effectively attenuated the Aβ1-42-induced cognitive deficits in spatial learning and memory of rats in Morris water maze test; (2) DU-14 prevented Aβ1-42-induced decrease in the cholinergic theta rhythm of hippocampal local field potential (LFP) in the CA1 region; (3) DU-14 protected hippocampal synaptic plasticity against Aβ1-42-induced suppression of long term potentiation (LTP). These results provide evidence for the neuroprotective action of DU-14 against neurotoxic Aβ, suggesting that up-regulation of endogenous DHEAS by DU-14 could be beneficial to the alleviation of Aβ-induced impairments in spatial memory and synaptic plasticity.

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

Memory loss and cognition decline are the main clinical manifestations of Alzheimers 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.

Sex Differences in Neuropathology and Cognitive Behavior in APP/PS1/tau Triple-Transgenic Mouse Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A–cAMP response element-binding protein (PKA-CREB) and p38–mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.

Cerebral inoculation of human A53T α-synuclein reduces spatial memory decline and amyloid-β aggregation in APP/PS1 transgenic mice of Alzheimer’s disease

Amyloid-β (Aβ) peptide and α-synuclein (α-syn) are major components of senile plaques in Alzheimers disease (AD) and Lewy bodies in Parkinsons disease (PD), respectively. Co-occurrence of Aβ and α-syn in the senile brains of AD and LB diseases suggests interactions between the two proteins. However, the significance of the overlapping deposition, especially the effects of α-syn on the Aβ aggregation, still remains to be clarified. In the present study, we investigated the effects of α-syn pre-formed fibrils (PFFs) injection on the cognitive behaviors and Aβ deposition in the brain of APP/PS1 transgenic AD mice by using Morris water maze (MWM) test, immunohistochemistry and western blot techniques. We found that APP/PS1 transgenic mice exhibited an obvious elevation in the α-syn load, as well as Aβ deposition in the brain compared with wild type of C57 BL littermates. 5 months after cerebral injection of exogenous α-syn, MWM tests showed an alleviation in cognitive impairments in APP/PS1 mice; western blot and immunohistochemistry experiments also exhibited a significant reduction in Aβ level in the brain of APP/PS1 mice injected with α-syn. These results suggest that α-syn aggregated in the brain of AD may act as a protective factor and defend the brain tissue from early Aβ deposition and cognitive deficits.

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

Alzheimers disease (AD) is the most common cause of dementia, and effective therapeutics are lacking. Colivelin (CLN), a novel, strong humanin derivative, is effective in vitro in preventing cell death induced by AD-causative genes and amyloid-β protein (Aβ) even at a low concentration. We recently demonstrated that intrahippocampal injection of CLN prevents Aβ25-35-induced deficits in spatial memory and synaptic plasticity in normal rats. Here, we further observed the effects of chronically intranasally (i.n.) administered CLN on cognitive behaviors and pathological hallmarks in 9-month-old APPswe/PS1dE9 (APP/PS1) AD mice using multiple behavioral tests and immunochemistry. The electrophysiological mechanism of CLN neuroprotection was also investigated by recording in vivo hippocampal long-term potentiation (LTP). CLN pretreatment effectively prevented impairments in new object recognition, working memory, and long-term spatial memory and reversed the depression of in vivo hippocampal LTP in APP/PS1 mice. Additionally, chronic application of CLN obviously reduced Aβ deposition in the hippocampus in APP/PS1 mice. These results indicate that CLN has strong neuroprotective effects on learning and memory behaviors in APP/PS1 mice and that this behavioral improvement is closely associated with the reduction of Aβ deposition and alleviation of LTP suppression in the hippocampus, supporting the potential of CLN for the prevention and treatment of AD.