Mei-Na Wu

Liraglutide protects against amyloid-β protein-induced impairment of spatial learning and memory in rats.

Type 2 diabetes mellitus is a risk factor of Alzheimers disease (AD), most likely linked to an impairment of insulin signaling in the brain. Liraglutide, a novel long-lasting glucagon-like peptide 1 (GLP-1) analog, facilitates insulin signaling and shows neuroprotective properties. In the present study, we analyzed the effects of liraglutide on the impairment of learning and memory formation induced by amyloid-β protein (Aβ), and the probable underlying electrophysiological and molecular mechanisms. We found that (1) bilateral intrahippocampal injection of Aβ(25-35) resulted in a significant decline of spatial learning and memory of rats in water maze tests, together with a serious depression of in vivo hippocampal late-phase long-term potentiation (L-LTP) in CA1 region of rats; (2) pretreatment with liraglutide effectively and dose-dependently protected against the Aβ(25-35)-induced impairment of spatial memory and deficit of L-LTP; (3) liraglutide injection also activated cAMP signal pathway in the brain, with a nearly doubled increase in the cAMP contents compared with control. These results strongly suggest that upregulation of GLP-1 signaling in the brain, such as application of liraglutide, may be a novel and promising strategy to ameliorate the learning and memory impairment seen in AD.

Requirement of α7 nicotinic acetylcholine receptors for amyloid beta protein-induced depression of hippocampal long-term potentiation in CA1 region of rats in vivo

The high density of senile plaques with amyloid beta protein (Aβ) and the loss of cholinergic neurons in the brain are the dominated pathological characteristics of Alzheimers disease (AD). However, the active center of Aβ, especially the cholinergic mechanism underlying the Aβ neurotoxicity, is mostly unknown. This study examined the effects of different Aβ fragments on hippocampal long‐term potentiation (LTP) and investigated its probable α7 nicotinic acetylcholine receptors (nAChRs) mechanism. The results show that: (1) intracerebroventicular injection of Aβ25–35 or Aβ31–35 significantly and similarly suppressed hippocampal LTP in CA1 region in rats; (2) choline, a selective α7 nAChR agonist, did not affect the LTP induction but enhanced LTP suppression induced by Aβ31–35; and (3) methyllycaconitine, a specific α7 nAChR antagonist, slightly suppressed hippocamal LTP but effectively prevented against Aβ31–35‐induced LTP depression in the presence of Aβ31–35. These results indicate that: (1) the amino acid sequence 31–35 of the Aβ peptide might be a shorter active sequence in the full length molecule; (2) α7 nAChRs are required for the Aβ‐induced suppression of hippocampal LTP. Thus, this study not only provides a new insight into the mechanism by which Aβ impairs synaptic plasticity but also strongly suggests that sequence 31–35 in Aβ molecule and α7 nAChRs in the brain might be potential therapeutic targets for the treatment of AD. Synapse 2011.

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.

Desipramine improves depression-like behavior and working memory by up-regulating p-CREB in Alzheimer’s disease associated mice

Aggregation of amyloid [Formula: see text] protein (A[Formula: see text] and progressive loss of memory are the main characteristics of Alzheimers disease (AD). It is noteworthy that approximately 40% of AD patients have depressive symptom. The close correlation between cognitive deficits and mental depression suggests a possibility that antidepression treatment might be beneficial to cognitive improvement in AD. The present study, by using tail-suspension test (TST), forced swimming, alternative electro-stimulus Y maze test and immunohistochemistry, examined the neuroprotective effects of desipramine, a newer generation tricyclic antidepressants (TCA), and investigated its possible molecular mechanism. The results showed that: (1) intra-hippocampal injection of A[Formula: see text] induced depression-like behavior and associative learning deficits in mice, with an increased mean immobility time in tail-suspension and forced swimming test and an increased mean error times in Y maze test; (2) after treatment with desipramine (10[Formula: see text]mg/kg, i.p.), the average immobility time significantly decreased, from [Formula: see text][Formula: see text]s in A[Formula: see text] group to [Formula: see text][Formula: see text]s in A[Formula: see text] plus desipramine group ([Formula: see text]) in TST and from [Formula: see text][Formula: see text]s to [Formula: see text][Formula: see text]s ([Formula: see text] or 9, [Formula: see text]) in forced swimming test, respectively;the mean error times of mice in Y maze test also significantly decreased, from [Formula: see text] in A[Formula: see text] group to [Formula: see text] in A[Formula: see text] plus desipramine group ([Formula: see text], [Formula: see text]); (3) desipramine administration significantly prevented against A[Formula: see text]-induced down-regulation of phosphorylated cAMP response element binding protein (p-CREB) in the hippocampus. These results indicate that A[Formula: see text] could concurrently mimic the depression-like behavior and working memory disorder in mice, while desipramine could effectively reverse both the deficits induced by A[Formula: see text]. The neuroprotection of desipramine may be involved in the up-regulation of p-CREB level in the hippocampus of mice.

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.

Amyloid β-protein suppressed nicotinic acetylcholine receptor-mediated currents in acutely isolated rat hippocampal CA1 pyramidal neurons

Amyloid β protein (Aβ) is responsible for the deficits of learning and memory in Alzheimers disease (AD). The high affinity between Aβ and nicotinic acetylcholine receptors (nAChRs) suggests that the impairment of cognitive function in AD might be involved in the Aβ‐induced damage of nAChRs. This study investigated the effects of Aβ fragments on nAChR‐mediated membrane currents in acutely isolated rat hippocampal pyramidal neurons by using whole‐cell patch clamp technique. The results showed that: (1) nonspecific nAChR agonist nicotine, selective α7 nAChR agonist choline, and α4β2 nAChR agonist epibatidine all effectively evoked inward currents in CA1 neurons at normal resting membrane potential, with different desensitization characteristics; (2) acute application of different concentrations (pM–μM) of Aβ25‐35, Aβ31‐35, or Aβ35‐31 alone did not trigger any membrane current, but pretreatment with 1 μM Aβ25‐35 and Aβ31‐35 similarly and reversibly suppressed the nicotine‐induced currents; (3) further, choline‐ and epibatidine‐induced currents were also reversibly suppressed by the Aβ pretreatment, but more prominent for the choline‐induced response. These results demonstrate that the functional activity of both α7 and α4β2 nAChRs in the membrane of acutely isolated hippocampal neurons was significantly downregulated by Aβ treatment, suggesting that nAChRs, especially α7 nAChRs, in the brain may be the important biological targets of neurotoxic Aβ in AD. In addition, the similar suppression of nAChR currents by Aβ25‐35 and Aβ31‐35 suggests that the sequence 31‐35 in Aβ molecule may be a shorter active center responsible for the neurotoxicity of Aβ in AD. Synapse, 2013.

A novel GLP‐1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease

Type 2 diabetes mellitus (T2DM) is an important risk factor for Alzheimers disease (AD). Glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) have been identified to be effective in T2DM treatment and neuroprotection. In this study, we further explored the effects of a novel unimolecular GLP‐1/GIP/Gcg triagonist on the cognitive behavior and cerebral pathology in the 7‐month‐old triple transgenic mouse model of AD (3xTg‐AD), and investigated its possible electrophysiological and molecular mechanisms. After chronic administration of the GLP‐1/GIP/Gcg triagonist (10 nmol/kg bodyweight, once daily, i.p.) for 30 days, open field, Y maze and Morris water maze tests were performed, followed by in vivo electrophysiological recording, immunofluorescence and Western blotting experiments. We found that the chronic treatment with the triagonist could improve long‐term spatial memory of 3xTg‐AD mice in Morris water maze, as well as the working memory in Y maze task. The triagonist also alleviated the suppression of long‐term potentiation (LTP) in the CA1 region of hippocampus. In addition, the triagonist significantly reduced hippocampal pathological damages, including amyloid‐β (Aβ) and phosphorylated tau aggregates, and upregulated the expression levels of S133p‐CREB, T286p‐CAMKII and S9p‐GSK3β in the hippocampus of the 3xTg‐AD mice. These results demonstrate for the first time that the novel GLP‐1/GIP/Gcg triagonist is efficacious in ameliorating cognitive deficits and pathological damages of 3xTg‐AD mice, suggesting that the triagonist might be potentially beneficial in the treatment of AD.

DA5-CH, a novel GLP-1/GIP dual agonist, effectively ameliorates the cognitive impairments and pathology in the APP/PS1 mouse model of Alzheimer's disease

Abstract Alzheimers disease (AD) is a progressive neurodegenerative disorder for which there is no cure. The early primary symptom of AD is the decline of memory ability, which gradually develops into complete dementia. Type 2 diabetes mellitus (T2DM) is an important risk factor of AD; and mimetics of the incretin hormone GLP‐1 developed to treat diabetes are being tested as a novel therapeutic strategy for AD. In the present study, we reported for the first time the neuroprotective effects of a novel GLP‐1/GIP dual agonist DA5‐CH that activates the incretin hormone GLP‐1 and GIP receptors in the APP/PS1 transgenic AD mouse model. We found that: (1) DA5‐CH administration effectively improved working‐memory and long‐term spatial memory of 9‐month‐old AD mice in Y‐maze and Morris water maze tests; (2) DA5‐CH also reduced hippocampal amyloid senile plaques and phosphorylated tau protein levels; (3) DA5‐CH basically reversed the deficits in hippocampal late‐phase long‐term potentiation; (4) DA5‐CH up‐regulated the levels of p‐PI3K and p‐AKT growth factor kinases and prevented excessive activation of p‐GSK3&bgr; in the hippocampus of APP/PS1 mice. Therefore, the neuroprotection of DA5‐CH in alleviating cognitive impairments and pathological damages might be associated with the improvement of hippocampal synaptic plasticity and activation of the PI3K/AKT signaling pathway. We propose that DA5‐CH may be beneficial for the treatment of AD patients, especially those with T2DM or hyperglycemia.

Co-injection of Aβ1-40 and ApoE4 impaired spatial memory and hippocampal long-term potentiation in rats

Apolipoprotein E4 (APOE4) allele located on chromosome 19 is a major genetic risk factor for developing Alzheimers disease (AD). However, the direct effects of ApoE4 on the cognitive function and long-term synaptic plasticity have not fully investigated. At the same time, although amyloid beta protein (Aβ)-ApoE complexes are principal components of AD-associated brain damage, there is still lack of in vivo study on the effects of co-existed Aβ1-40 and ApoE4. In the present study, we examined the effects of ApoE4 on the spatial memory and hippocampal long term potentiation (LTP) by using Morris water maze test and in vivo field potential recording, compared the neurotoxicity of Aβ1-40 and ApoE4, and investigated the effects of co-application of Aβ1-40 and ApoE4 on cognitive behavior and synaptic plasticity. The results showed that intracerebrovenrticular (i.c.v.) injection of Aβ1-40 or ApoE4 significantly and similarly impaired spatial learning and memory, and depressed the high-frequency stimulus (HFS) induced LTP. Importantly, compared to the effects of Aβ1-40 or ApoE4 alone, co-injection of Aβ1-40 and ApoE4 produced much heavier damages in cognitive behaviors and long term synaptic plasticity. These results demonstrated that ApoE4 not only exerted direct neurotoxicity but also enhanced the neurotoxicity of Aβ1-40 on spatial cognitive function and hippocampal LTP, which maybe partly elucidates the mechanism by which APOE4 allele exerted negative effects as a major genetic risk factor for developing AD.