DAla2-GIP-GLU-PAL Protects Against Cognitive Deficits and Pathology in APP/PS1 Mice by Inhibiting Neuroinflammation and Upregulating cAMP/PKA/CREB Signaling Pathways

2021 ◽  
pp. 1-19
Author(s):  
Li Yuan ◽  
Jun Zhang ◽  
Jun-Hong Guo ◽  
Christian Holscher ◽  
Jun-Ting Yang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Cognitive Function ◽  
Late Phase ◽  
Long Term Potentiation ◽  
Morris Water Maze Test ◽  
Signal Molecules ◽  
Function Type ◽  
Maze Test ◽  
Tnf Α

Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function. Type 2 diabetes mellitus (T2DM) is an important risk factor for AD. Glucose-dependent insulinotropic polypeptide (GIP) has been identified to be effective in T2DM treatment and neuroprotection. Objective: The present study investigated the neuroprotective effects and possible mechanisms of DAla2GIP-Glu-PAL, a novel long-lasting GIP analogue, in APP/PS1 AD mice. Methods: Multiple behavioral tests were performed to examine the cognitive function of mice. In vivo hippocampus late-phase long-term potentiation (L-LTP) was recorded to reflect synaptic plasticity. Immunohistochemistry and immunofluorescence were used to examine the Aβ plaques and neuroinflammation in the brain. IL-1β, TNF-α, and cAMP/PKA/CREB signal molecules were also detected by ELISA or western blotting. Results: DAla2GIP-Glu-PAL increased recognition index (RI) of APP/PS1 mice in novel object recognition test, elevated spontaneous alternation percentage of APP/PS1 mice in Y maze test, and increased target quadrant swimming time of APP/PS1 mice in Morris water maze test. DAla2GIP-Glu-PAL treatment enhanced in vivo L-LTP of APP/PS1 mice. DAla2GIP-Glu-PAL significantly reduced Aβ deposition, inhibited astrocyte and microglia proliferation, and weakened IL-1β and TNF-α secretion. DAla2GIP-Glu-PAL also upregulated cAMP/PKA/CREB signal transduction and inhibited NF-κB activation in the hippocampus of APP/PS1 mice. Conclusion: DAla2GIP-Glu-PAL can improve cognitive behavior, synaptic plasticity, and central pathological damage in APP/PS1 mice, which might be associated with the inhibition of neuroinflammation, as well as upregulation of cAMP-/PKA/CREB signaling pathway. This study suggests a potential benefit of DAla2GIP-Glu-PAL in the treatment of AD.

Protective Effects of DAla2-GIP-GLU-PAL against Cognitive Deficits and Amyloid Deposition in APP/PS1 AD Mice Associated with Reduction of Neuroinflammation

2020 ◽  
Author(s):  
Jinshun Qi ◽  
Li Yuan ◽  
Jun Zhang ◽  
Christian Holscher ◽  
Jun-Ting Yang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Object Recognition ◽  
Cognitive Function ◽  
Late Phase ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Cognitive Behaviors ◽  
The Brain

Abstract Background Alzhermer’s disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function and high-density deposition of amyloid-β (Aβ) plaques in the brain. Type 2 diabetes mellitus (T2DM) is an important risk factor for AD. Glucose-dependent insulinotropic polypeptide (GIP) has been identified to be effective in T2DM treatment and neuroprotection. The present study further investigated the neuroprotective effects of a novel long lasting GIP analogue DAla2GIP-Glu-PAL in 9-month-old APP swe /PS1 dE9 (APP/PS1) AD mice. Methods Multiple behavioral tests including new object recognition, Y maze and Morris water maze were performed to examine the cognitive function of mice. In vivo hippocampal late-phase long-term potentiation (L-LTP) was recorded to reflect synaptic plasticity. Immunohistochemistry and immunofluorescence were used to examine the Aβ plaques and neuroinflammation in the brain. The expression levels of cAMP, S99 p-PKA, S133 p-CREB, S468 NF-κBp65 and IL-1β were detected by western blotting or ELISA. Results DAla2GIP-Glu-PAL effectively improved cognitive behaviors and synaptic plasticity of APP/PS1 mice, with increased new object recognition, spontaneous alternation and target quadrant swimming time, as well as enhanced in vivo hippocampal L-LTP. DAla2GIP-Glu-PAL significantly reduced Aβ deposition and inhibited astrocyte proliferation, IL-1β secretion and NF-κB activation. Besides, . DAla2GIP-Glu-PAL also up-regulated cAMP/PKA/CREB signal transduction in the hippocampus of APP/PS1 mice. Conclusion DAla2GIP-Glu-PAL improves cognitive behaviors, long-term synaptic plasticity and pathological damages in APP/PS1 mice, which are associated with the reduction of neuroinflammation and the up-regulation of cAMP/PKA/CREB signaling in the hippocampus. This study suggests a potential benefit of DAla2GIP-Glu-PAL in the treatment of AD.

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

2021 ◽  
pp. 1-15
Author(s):  
Xu-Dong Yan ◽  
Xue-Song Qu ◽  
Jing Yin ◽  
Jin Qiao ◽  
Jun Zhang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Cognitive Deficits ◽  
Morris Water Maze Test ◽  
Amyloid Β Protein ◽  
Maze Test ◽  
Anti Inflammatory ◽  
Electrophysiological Mechanism ◽  
Proinflammatory Factors

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-β protein (Aβ) 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-1β, 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.

scholarly journals Simvastatin impairs hippocampal synaptic plasticity and cognitive function in mice

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yujun Guo ◽  
Guichang Zou ◽  
Keke Qi ◽  
Jin Jin ◽  
Lei Yao ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Cognitive Function ◽  
Memory Function ◽  
Long Term Potentiation ◽  
Drug Discontinuation ◽  
Hippocampal Synaptic Plasticity ◽  
Term Potentiation ◽  
The Central Nervous System

AbstractLipophilic statins which are blood brain barrier (BBB) permeable are speculated to affect the cholesterol synthesis and neural functions in the central nervous system. However, whether these statins can affect cholesterol levels and synaptic plasticity in hippocampus and the in vivo consequence remain unclear. Here, we report that long-term subcutaneous treatments of simvastatin significantly impair mouse hippocampal synaptic plasticity, reflected by the attenuated long-term potentiation of field excitatory postsynaptic potentials. The simvastatin administration causes a deficiency in recognition and spatial memory but fails to affect motor ability and anxiety behaviors in the mice. Mass spectrometry imaging indicates a significant decrease in cholesterol intensity in hippocampus of the mice receiving chronic simvastatin treatments. Such effects of simvastatin are transient because drug discontinuation can restore the hippocampal cholesterol level and synaptic plasticity and the memory function. These findings may provide further clues to elucidate the mechanisms of neurological side effects, especially the brain cognitive function impairment, caused by long-term usage of BBB-permeable statins.

scholarly journals Simvastatin Impairs Hippocampal Synaptic Plasticity and Cognitive Function in Mice

2020 ◽  
Author(s):  
Yujun Guo ◽  
Guichang Zou ◽  
Jin Jin ◽  
Lei Yao ◽  
Keke Qi ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Cognitive Function ◽  
Memory Function ◽  
Long Term Potentiation ◽  
Drug Discontinuation ◽  
Hippocampal Synaptic Plasticity ◽  
Term Potentiation ◽  
The Central Nervous System

Abstract Lipophilic statins which are blood brain barrier (BBB) permeable are speculated to affect the cholesterol synthesis and neural functions in the central nervous system. However, whether these statins can affect cholesterol levels and synaptic plasticity in hippocampus and the in vivo consequence remain unclear. Here, we report that long-term subcutaneous treatments of simvastatin significantly impair mouse hippocampal synaptic plasticity, reflected by the attenuated long-term potentiation of field excitatory postsynaptic potentials. The simvastatin administration causes a deficiency in recognition and spatial memory but fails to affect motor ability and anxiety behaviors in the mice. Mass spectrometry imaging indicates a significant decrease in cholesterol intensity in hippocampus of the mice receiving chronic simvastatin treatments. Such effects of simvastatin are transient because drug discontinuation can restore the hippocampal cholesterol level and synaptic plasticity and the memory function. These findings may provide further clues to elucidate the mechanisms of neurological side effects, especially the brain cognitive function impairment, caused by long-term usage of BBB-permeable statins.

Brivaracetam Prevents the Over-expression of Synaptic Vesicle Protein 2A and Rescues the Deficits of Hippocampal Long-term Potentiation In Vivo in Chronic Temporal Lobe Epilepsy Rats

2020 ◽  
Vol 17 (4) ◽  
pp. 354-360 ◽  
Author(s):  
Yu-Xing Ge ◽  
Ying-Ying Lin ◽  
Qian-Qian Bi ◽  
Yu-Juan Chen
Keyword(s):  
Synaptic Plasticity ◽  
Temporal Lobe Epilepsy ◽  
Synaptic Vesicle ◽  
Long Term Potentiation ◽  
Synaptic Dysfunction ◽  
Over Expression ◽  
Term Potentiation ◽  
Synaptic Vesicle Protein 2A

Background: Patients with temporal lobe epilepsy (TLE) usually suffer from cognitive deficits and recurrent seizures. Brivaracetam (BRV) is a novel anti-epileptic drug (AEDs) recently used for the treatment of partial seizures with or without secondary generalization. Different from other AEDs, BRV has some favorable properties on synaptic plasticity. However, the underlying mechanisms remain elusive. Objective: The aim of this study was to explore the neuroprotective mechanism of BRV on synaptic plasticity in experimental TLE rats. Methods: The effect of chronic treatment with BRV (10 mg/kg) was assessed on Pilocarpine induced TLE model through measurement of the field excitatory postsynaptic potentials (fEPSPs) in vivo. Differentially expressed synaptic vesicle protein 2A (SV2A) were identified with immunoblot. Then, fast phosphorylation of synaptosomal-associated protein 25 (SNAP-25) during long-term potentiation (LTP) induction was performed to investigate the potential roles of BRV on synaptic plasticity in the TLE model. Results: An increased level of SV2A accompanied by a depressed LTP in the hippocampus was shown in epileptic rats. Furthermore, BRV treatment continued for more than 30 days improved the over-expression of SV2A and reversed the synaptic dysfunction in epileptic rats. Additionally, BRV treatment alleviates the abnormal SNAP-25 phosphorylation at Ser187 during LTP induction in epileptic ones, which is relevant to the modulation of synaptic vesicles exocytosis and voltagegated calcium channels. Conclusion: BRV treatment ameliorated the over-expression of SV2A in the hippocampus and rescued the synaptic dysfunction in epileptic rats. These results identify the neuroprotective effect of BRV on TLE model.

scholarly journals Effects of Pueraria candollei var mirifica (Airy Shaw and Suvat.) Niyomdham on Ovariectomy-Induced Cognitive Impairment and Oxidative Stress in the Mouse Brain

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3442
Author(s):  
Yaowared Chulikhit ◽  
Wichitsak Sukhano ◽  
Supawadee Daodee ◽  
Waraporn Putalun ◽  
Rakvajee Wongpradit ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cognitive Impairment ◽  
Morris Water Maze Test ◽  
Object Recognition Test ◽  
Pueraria Mirifica ◽  
Beneficial Effects ◽  
Maze Test ◽  
Y Maze ◽  
Tnf Α ◽  
17Β Estradiol

The effects of the phytoestrogen-enriched plant Pueraria mirifica (PM) extract on ovari-ectomy (OVX)-induced cognitive impairment and hippocampal oxidative stress in mice were investigated. Daily treatment with PM and 17β-estradiol (E2) significantly elevated cognitive behavior as evaluated by using the Y maze test, the novel object recognition test (NORT), and the Morris water maze test (MWM), attenuated atrophic changes in the uterus and decreased serum 17β-estradiol levels. The treatments significantly ameliorated ovariectomy-induced oxidative stress in the hippocampus and serum by a decrease in malondialdehyde (MDA), an enhancement of superoxide dismutase, and catalase activity, including significantly down-regulated expression of IL-1β, IL-6 and TNF-α proinflammatory cytokines, while up-regulating expression of PI3K. The present results suggest that PM extract suppresses oxidative brain damage and dysfunctions in the hippocampal antioxidant system, including the neuroinflammatory system in OVX animals, thereby preventing OVX-induced cognitive impairment. The present results indicate that PM exerts beneficial effects on cognitive deficits for which menopause/ovariectomy have been implicated as risk factors.

scholarly journals Protective effects and mechanisms of high-dose vitamin C on sepsis-associated cognitive impairment in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ning Zhang ◽  
Wei Zhao ◽  
Zhen-Jie Hu ◽  
Sheng-Mei Ge ◽  
Yan Huo ◽  
...  
Keyword(s):  
Vitamin C ◽  
Escape Latency ◽  
Morris Water Maze Test ◽  
Protective Mechanism ◽  
High Dose ◽  
Maze Test ◽  
Tnf Α ◽  
Histopathologic Changes ◽  
High Dose Vitamin ◽  
Necrosis Factor

AbstractSepsis survivors present long-term cognitive deficits. The present study was to investigate the effect of early administration of high-dose vitamin C on cognitive function in septic rats and explore its possible cerebral protective mechanism. Rat sepsis models were established by cecal ligation and puncture (CLP). Ten days after surgery, the Morris water maze test was performed to evaluate the behavior and cognitive function. Histopathologic changes in the hippocampus were evaluated by nissl staining. The inflammatory cytokines, activities of antioxidant enzymes (superoxide dismutase or SOD) and oxidative products (malondialdehyde or MDA) in the serum and hippocampus were tested 24 h after surgery. The activity of matrix metalloproteinase-9 (MMP-9) and expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) in the hippocampus were measured 24 h after surgery. Compared with the sham group in the Morris water maze test, the escape latency of sepsis rats was significantly (P = 0.001) prolonged in the navigation test, whereas the frequency to cross the platform and the time spent in the target quadrant were significantly (P = 0.003) reduced. High-dose vitamin C significantly decreased the escape latency (P = 0.01), but increased the time spent in the target quadrant (P = 0.04) and the frequency to cross the platform (P = 0.19). In the CLP+ saline group, the pyramidal neurons were reduced and distributed sparsely and disorderly, the levels of inflammatory cytokines of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 in the serum and hippocampus were significantly increased (P = 0.000), the blood brain barrier (BBB) permeability in the hippocampus was significantly (P = 0.000) increased, the activities of SOD in the serum and hippocampus were significantly (P = 0.000 and P = 0.03, respectively) diminished while the levels of MDA in the serum and hippocampus were significantly (P = 0.007) increased. High-dose vitamin C mitigated hippocampus histopathologic changes, reduced systemic inflammation and neuroinflammation, attenuated BBB disruption, inhibited oxidative stress in brain tissue, and up-regulated the expression of nuclear and total Nrf2 and HO-1. High-dose vitamin C significantly (P < 0.05) decreased the levels of tumor necrosis factor- (TNF)-α, interleukin-6 (IL-6), MDA in the serum and hippocampus, and the activity of MMP-9 in the hippocampus, but significantly (P < 0.05) increased the levels of SOD, the anti-inflammatory cytokine (IL-10) in the serum and hippocampus, and nuclear and total Nrf2, and HO-1 in the hippocampus. In conclusion, high-dose vitamin C can improve cognition impairment in septic rats, and the possible protective mechanism may be related to inhibition of inflammatory factors, alleviation of oxidative stress, and activation of the Nrf2/HO-1 pathway.

scholarly journals Protein kinase D promotes plasticity-induced F-actin stabilization in dendritic spines and regulates memory formation

2015 ◽  
Vol 210 (5) ◽  
pp. 771-783 ◽  
Author(s):  
Norbert Bencsik ◽  
Zsófia Szíber ◽  
Hanna Liliom ◽  
Krisztián Tárnok ◽  
Sándor Borbély ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Protein Kinase ◽  
Dendritic Spines ◽  
Morphological Changes ◽  
Long Term Potentiation ◽  
Memory Formation ◽  
Protein Kinase D

Actin turnover in dendritic spines influences spine development, morphology, and plasticity, with functional consequences on learning and memory formation. In nonneuronal cells, protein kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro models of neuronal plasticity, such as glycine-induced chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term depolarization block by KCl, leading to homeostatic morphological changes, we show that actin stabilization needed for the enlargement of dendritic spines is dependent on PKD activity. Consequently, impaired PKD functions attenuate activity-dependent changes in hippocampal dendritic spines, including LTP formation, cause morphological alterations in vivo, and have deleterious consequences on spatial memory formation. We thus provide compelling evidence that PKD controls synaptic plasticity and learning by regulating actin stability in dendritic spines.

scholarly journals Synaptic plasticity in the mesolimbic dopamine system

2003 ◽  
Vol 358 (1432) ◽  
pp. 815-819 ◽  
Author(s):  
Mark J. Thomas ◽  
Robert C. Malenka
Keyword(s):  
Synaptic Plasticity ◽  
Drugs Of Abuse ◽  
Neural Circuit ◽  
Long Term Potentiation ◽  
Brain Regions ◽  
Mesolimbic Dopamine ◽  
Dopamine System ◽  
Mesolimbic Dopamine System

Long-term potentiation (LTP) and long-term depression (LTD) are thought to be critical mechanisms that contribute to the neural circuit modifications that mediate all forms of experience-dependent plasticity. It has, however, been difficult to demonstrate directly that experience causes long-lasting changes in synaptic strength and that these mediate changes in behaviour. To address these potential functional roles of LTP and LTD, we have taken advantage of the powerful in vivo effects of drugs of abuse that exert their behavioural effects in large part by acting in the nucleus accumbens (NAc) and ventral tegmental area (VTA); the two major components of the mesolimbic dopamine system. Our studies suggest that in vivo drugs of abuse such as cocaine cause long-lasting changes at excitatory synapses in the NAc and VTA owing to activation of the mechanisms that underlie LTP and LTD in these structures. Thus, administration of drugs of abuse provides a distinctive model for further investigating the mechanisms and functions of synaptic plasticity in brain regions that play important roles in the control of motivated behaviour, and one with considerable practical implications.

Nicotine Enhances the Depressive Actions of Aβ1–40 on Long-Term Potentiation in the Rat Hippocampal CA1 Region In Vivo

2003 ◽  
Vol 89 (6) ◽  
pp. 2917-2922 ◽  
Author(s):  
D. B. Freir ◽  
C. E. Herron
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
High Affinity ◽  
Ca1 Region ◽  
Α7 Nachr ◽  
Term Potentiation ◽  
Significant Depression

Hippocampal long-term potentiation (LTP) is a form of synaptic plasticity used as a cellular model of memory. Beta amyloid (Aβ) is involved in Alzheimer's disease (AD), a neurode-generative disorder leading to cognitive deficits. Nicotine is also claimed to act as a cognitive enhancer. Aβ is known to bind with high affinity to the α7-nicotinic acetylcholine receptor (nAChR). Here we have investigated the effect of intracerebroventricular (icv) injection of the endogenous peptide Aβ1–40 on LTP in area CA1 of urethananesthetized rats. We also examined the effect of Aβ12–28 (icv), which binds with high affinity to the α7-nAChR and the specific α7-nAChR antagonist methyllycaconitine (MLA) on LTP. We found that Aβ12–28 had no effect on LTP, whereas MLA depressed significantly LTP, suggesting that activation of the α7-nAChR is a requirement for LTP. Within the in vivo environment, where other factors may compete with Aβ12–28 for binding to α7-nAChR, it does not appear to modulate LTP. To determine if the depressive action of Aβ1–40 on LTP could be modulated by nicotine, these agents were also co-applied. Injection of 1 or 10 nmol Aβ1–40 caused a significant depression of LTP, whereas nicotine alone (3 mg/kg) had no effect on LTP. Co-injection of nicotine with Aβ1–40 1 h prior to LTP induction caused a further significant depression of LTP compared with Aβ1–40 alone. These results demonstrate that nicotine enhances the deficit in LTP produced by Aβ1–40. This then suggests that nicotine may exacerbate the depressive actions of Aβ on synaptic plasticity in AD.

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