Adiponectin Ameliorates Cognitive Behaviors and in vivo Synaptic Plasticity Impairments in 3xTg-AD Mice.

BACKGROUND: Cognitive deficit is mainly clinical characteristic of Alzheimer's disease (AD). Recent reports showed adiponectin and its analogues could reverse cognitive impairments, lower amyloid-ß protein (Aß) deposition, and exert anti-inflammatory effects in different APP/PS1 AD model mice mainly exhibiting amyloid plaque pathology. However, the potential in vivo electrophysiological mechanism of adiponectin protecting against cognitive deficits in AD and the neuroprotective effects of adiponectin on 3xTg-AD mice including both plaque and tangle pathology are still unclear. OBJECTIVE: To observe the effects of adiponectin treatment on cognitive deficits in 3xTg-AD mice, investigate its potential in vivo electrophysiological mechanism, and testify its anti-inflammatory effects. METHODS: Barnes maze test, Morris water maze test, and fear conditioning test were used to evaluate the memory-ameliorating effects of adiponectin on 3xTg-AD mice. In vivo hippocampal electrophysiological recording was used to observe the change of basic synaptic transmission, long-term potentiation, and long-term depression. Immunohistochemistry staining and western blot were used to observe the activation of microglia and astroglia, and the expression levels of proinflammatory factors and anti-inflammtory factor IL-10. RESULTS: Adiponectin treatment could alleviate spatial memory and conditioned fear memory deficits observed in 3xTg-AD mice, improve in vivo LTP depression and LTD facilitation, inhibit overactivation of microglia and astroglia, decrease the expression of proinflammatory factors NF- κB and IL-1ß, and increase the expression level of IL-10 in the hippocampus of 3xTg-AD mice. CONCLUSION: Adiponectin could ameliorate cognitive deficits in 3xTg-AD mice through improving in vivo synaptic plasticity impairments and alleviating neuroinflammation in the hippocampus of 3xTg-AD mice.

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 Alzheimer's 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-ß (Aß) and phosphorylated tau aggregates, and upregulated the expression levels of S133 p-CREB, T286 p-CAMKII and S9 p-GSK3ß 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.

[GLP-1/GIP/Gcg receptor Triagonist improves the cognitive behaviors in triple-transgenic mice of Alzheimer's disease].

Alzheimer's disease (AD) is a progressively neurodegenerative disorder, which seriously affects human health but is still irreversible up to now. Recent studies indicate that type 2 diabetes mellitus (T2DM) is an important risk factor for AD, and the drugs used for treatment of T2DM have shown some neuroprotective effects in the treatment of AD. Glucagon-like peptide-1 (GLP-1)/ glucose-dependent insulinotropic polypeptide (GIP)/glucagon (Gcg) receptor Triagonist is a new monomeric polypeptide equally activating the GLP-1/GIP/Gcg receptors, which is built on the basis of GLP-1/Gcg receptor coagonist core sequence, and incorporated with partial amino acids of GIP. Recently, the Triagonist has been reported to be effective in alleviating diabetic complications in rodent models of obesity. The present study observed for the first time the cognitive improvement effects of the Triagonist in the triple-transgenic AD mice (3xTg-AD) by using multiple behavioral techniques, and explored its probable molecular mechanisms using ELISA and Western blot. The results showed that the chronic treatment with the Triagonist (i.p.) significantly reversed the impairments in working memory of 3xTg-AD mice, with an obvious increase in the percentage of correct spontaneous alternation in the Y maze; the Triagonist treatment also improved long-term spatial memory and re-learning ability of 3xTg-AD mice in classical Morris water maze and reverse water maze tests, with decreased escape latency in under water platform tests and increased swimming time in probe tests. ELISA and Western blot experiments showed that the Triagonist up-regulated the levels of cAMP, PKA and p-CREB in the hippocampus of 3xTg-AD mice. These results indicate that GLP-1/GIP/Gcg receptor Triagonist can improve the cognitive behaviors in 3xTg-AD mice, and the up-regulation of hippocampal cAMP/PKA/CREB signal pathway may mediate the neuroprotection of the Triagonist, suggesting that the GLP-1/GIP/Gcg receptor Triagonist may be a novel therapeutic strategy for the treatment of AD.

[Expressions of synaptophysin and BDNF/Trk-B in cerebellum of APPswe/PS1dE9 transgenic mice].

OBJECTIVE: To observe the expressions of synaptophysin and BDNF/Trk-B in cerebellum of APPswe/PS1dE9 transgenic mice. METHODS: The healthy 9-month old APP/PS1 male mice (n1) and the same wild type male mice(n2) were divided into two groups, APP/PS1 group and wild-type(WT) group. The expressions of synaptophysin and brain-derived neurotrophic factor/tyrosine kinase B (BDNF/Trk-B) in cerebellum were determined by Western blot (n1=6; n2=6) and immunohistochemical(n1=4; n2=4).The possible synaptic changes in APP/PS1 group were observed by using electron microscopy. RESULTS: Compared with WT group, the expressions of synaptophsin and BDNF/Trk-B in cerebellum were decreased in APP/PS1 group. Increased width of the synaptic cleft and decreased thickness of postsynaptic density were also observed. CONCLUSIONS: In APP/PS1 group, expressions of synaptophsin and BDNF/Trk-B in cerebellum were decreased; changes in ultrastructure of synapses seemed to be widespread alterations. These findings suggest a possible association between expression of BDNF/TrkB and synaptic plasticity in AD cerebellum.

[Effects of adiponectin on the anxiety and memory impairment in triple transgenic Alzheimer's disease model mice].

OBJECTIVE: To investigate the effects of adiponectin (APN) on anxiety and memory impairment of 9-month-old triple transgenic Alzheimer's disease (3xTg-AD) model mice. METHODS: The 9-month-old 3xTg-AD mice and C57BL/6J mice were randomly divided into four groups (n=8 for each group):Wild type(WT)+Saline, 3xTg-AD +Saline, WT+APN and 3xTg-AD +APN group. All mice were implanted cannula in lateral ventricle and each mouse was intracerebroventricular injected with adiponectin or saline under free moving condition after 7 days recovery. The anxiety and memory ability of each mouse were observed by using open field test, object recognition task and Y-maze test. RESULTS: ①In the open field test, compared to WT+Saline group, the time of 3xTg-AD +Saline mice spent in center was significantly decreased, and the time spent in periphery was obviously increased. However, APN treatment effectively reversed the phenomenon appeared in 3xTg-AD mice, indicating that APN could alleviate the anxiety observed in 3xTg-AD mice. ②In novel object recognition task, the discrimination index of 3xTg-AD+Saline group was (-16.7±10.1)%, significantly lower than (18.0±8.2)% in WT+Saline group (P<0.01) and (15.7±8.8)% in 3xTg-AD+APN group (P<0.01), which indicated that APN could effectively prevent the recognition memory impairment in 3xTg mice. ③In Y-maze test, the spontaneous alternation rate of 3xTg-AD +Saline group was (40.0±1.7)%,significantly lower than (56.6±4.6)% in WT+Saline group and (53.9±5.6)% in 3xTg-AD +APN group (P<0.01), which indicated that APN could prevent working memory impairment in 3xTg-AD mice. CONCLUSIONS: Adiponectin could effectively alleviate the anxiety and reverse the impairment of recognition memory and working memory of 9-month-old 3xTg-AD mice, and might play an important role in the prevention and treatment of AD.

[Dual co-agonist CI-1206 antagonizes Aß1-42-induced impairments in spatial learning and memory in mice].

OBJECTIVE: To study the neuroprotective effects of a novel GIP/GLP-1 receptor dual agonist CI-1206 against Aß1-42-induced impairments in spatial working memory and long term memory in mice. METHODS: C57 mice, after receiving intracerebralventricular (i.c.v.) injection of Aß1-42 and intraperitoneal injection of CI-1206, were divided into the following groups:saline+D-PBS, Aß1-42+saline, CI-1206+D-PBS and Aß1-42+CI-1206 group (n=12). Y maze spontaneous alternation of mice was tested to assess short term working memory, and Morris water maze task was used to assess long term reference memory. RESULTS: ①The percentage of right alternation of mice in Aß1-42+saline group was significantly decreased, while the percentage in Aß1-42+CI-1206 group was significantly larger than that in Aß1-42 alone group (P<0.05). ②In Morris water maze test, the escape latency of mice in Aß1-42+saline group showed a significant increase, with a significant decline in swimming time in target quadrant. Treatment with CI-1206 significantly antagonized these detrimental effects induced by Aß1-42. ③Aß1-42 and CI-1206 did not affect the motor ability and vision of mice. CONCLUSIONS: I.C.V. administration of Aß1-42 impaired the short term and long term spatial memory of mice, while CI-1206 could effectively antagonize the detrimental effects.

[Role of interleukin-1 receptor antagonist in protecting kidney from injury induced by asphyxia in neonatal rats].

OBJECTIVE: To observe the role of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in protecting kidney from injury induced by asphyxia in neonatal rats. METHODS: Neonatal rats were used as experimental animals. The changes in intrarenal inflammatory response and renal injury were examined in the control group (n=13), and 2, 24 and 48 hours after asphyxia followed by normal saline treatment in those treated with rhIL-1ra. RESULTS: In normal saline group, the white blood cell count, the blood interleukin-1 (IL-1), IL-8, IL-6, nitric oxide (NO), endothelin (ET-1) levels, and the renal coefficient (LRC), the scores of injured tubules of the left kidney were significantly increased at 2 hours (n=10), 24 hours (n=11), and 48 hours (n=10, P<0.05 or P<0.01). Compared with the normal saline group, the levels of the above parameters, except IL-6, were significantly decreased in rhIL-1ra treatment group at the same time points (P<0.05 or P<0.01). Serum IL-6 at 24 hours and 48 hours was also decreased in rhIL-1ra treatment group significantly (P<0.05 or P<0.01). CONCLUSION: The results suggest that rhIL-1ra may protect renal injury after asphyxia via inhibiting intrarenal inflammatory response.