Ethyl pyruvate prevents long-term stress-induced cognitive decline and modulates Akt/GSK-3ß signaling.

Stress is an inevitable part of life and, simultaneously, a stimulus that can trigger various neuropsychiatric disorders. Therefore, proper stress management is essential for maintaining a healthy life. In this study, we investigated the suppression of stress-induced cognitive deficit by controlling changes in synaptic plasticity caused by stress and confirmed that ethyl pyruvate (EP) has such an effect. Corticosterone, a stress hormone, suppresses long-term potentiation (LTP) in mouse acute hippocampal slices. EP blocked the LTP inhibitory effect of corticosterone by regulating GSK-3ß function. Restraint stress for 2 weeks increased the anxiety levels and caused the cognitive decline in the experimental animals. Administration of EP for 14 days did not affect the increase in anxiety caused by stress but improved cognitive decline caused by stress. In addition, the decrease in neurogenesis and synaptic function deficits in the hippocampus, which cause of cognitive decline due to stress, were improved by EP administration. These effects appear via regulation of Akt/GSK-3ß signaling, as in in vitro studies. These results suggest that EP prevents stress-induced cognitive decline through the modulation of Akt/GSK-3ß-mediated synaptic regulation.

Phyllodulcin improves hippocampal long-term potentiation in 5XFAD mice.

Alzheimer's disease (AD) is a well-known neurodegenerative brain disease, and no curative treatment has yet been developed. The main symptoms include various brain lesions, caused by amyloid ß (Aß) aggregation, and cognitive decline. Therefore, it is believed that substances that control Aß will inhibit the onset of Alzheimer's disease and slow its progression. In this study, the effect of phyllodulcin, a major component of hydrangea, on Aß aggregation and brain pathology in an animal model of AD was studied. Phyllodulcin inhibited the aggregation of Aß and decomposed the pre-aggregated Aß in a concentration-dependent manner. In addition, it inhibited the cytotoxicity of Aß aggregates. Oral administration of phyllodulcin improved Aß-induced memory impairments in normal mice, reduced Aß deposition in the hippocampus, inhibited the activation of microglia and astrocytes, and improved synaptic plasticity in 5XFAD mice. These results suggest that phyllodulcin may be a candidate for the treatment of AD.

Agmatine relieves behavioral impairments in Fragile X mice model.

BACKGROUND: Fragile X syndrome (FXS) is the most common heritable form of neurodevelopmental disorder, which is caused by the loss of fragile X mental retardation protein (FMRP) expression. Despite the unceasing efforts to develop therapeutic agents against FXS based on the pathophysiological changes observed in animal models of FXS and human patients, therapeutic candidates including mGluR signaling modulators have failed to provide sufficient effects. Based on the recent successful demonstration of an endogenous polyamine, agmatine, to improve the autism-like symptoms in the valproic acid animal model of autism, we investigated the effects of agmatine against FXS symptoms using Fmr1 knockout (KO) mice. METHODS: We used male Fmr1 KO mice for behavioral tests such as marble burying, open-field test, memory tasks, social interaction tests and startle response to confirm the symptoms of FXS. We also checked the electrophysiological profile of neural activity in agmatine-treated Fmr1 KO mice. RESULTS: Agmatine reversed the compulsion, learning and memory deficits, hyperactivity, aberrant social interaction, and communication deficit in Fmr1 KO mice while it normalized the aberrant LTP and LTD in the hippocampus. CONCLUSIONS: The results highlight the potential of agmatine's novel disease-ameliorating effects in FXS, which warrants further studies to ascertain whether these findings translate into clinical effects in FXS patients.

Hyperoside improves learning and memory deficits by amyloid ß1-42 in mice through regulating synaptic calcium-permeable AMPA receptors.

Alzheimer's disease (AD) is the most common degenerative disease and is indicative of dementia. The cerebral accumulation of amyloid ß (Aß), a crucial factor in AD, initiates synaptic and cognitive dysfunction. Therefore, the elevation of synaptic and cognitive functions may help manage dementia in AD. In this study, we suggest hyperoside as a synaptic function- and memory-enhancing agent. Hyperoside enhanced learning and memory in passive avoidance and object recognition tasks. Hyperoside facilitated synaptic long-term potentiation (LTP) in acute hippocampal slices. IEM-1460, a calcium-permeable amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) antagonist, blocked the facilitation effect of hyperoside. Hyperoside also induced N-methyl-d-aspartate receptor (NMDAR)-independent LTP, which was blocked by IEM-1460, suggesting the involvement of CP-AMPARs in the synaptic effects of hyperoside-mediated LTP. PKI (a PKA inhibitor) or SQ22536 (adenylyl cyclase, an AC inhibitor) blocked hyperoside-facilitated LTP and hyperoside-induced NMDAR-independent LTP. Hyperoside-enhanced learning and memory were blocked by IEM-1460, suggesting the involvement of CP-AMPARs in the effect of hyperoside on learning and memory. Finally, hyperoside ameliorated Aß-induced memory impairments in an AD mouse model. These results suggest that hyperoside enhances learning and memory, and this may be due to the effect of CP-AMPARs.

Eugenitol ameliorates memory impairments in 5XFAD mice by reducing Aß plaques and neuroinflammation.

Alzheimer's disease (AD) is caused by various pathological mechanisms; therefore, it is necessary to develop drugs that simultaneously act on multiple targets. In this study, we investigated the effects of eugenitol, which has anti-amyloid ß (Aß) and anti-neuroinflammatory effects, in an AD mouse model. We found that eugenitol potently inhibited Aß plaque and oligomer formation. Moreover, eugenitol dissociated the preformed Aß plaques and reduced Aß-induced nero2a cell death. An in silico docking simulation study showed that eugenitol may interact with Aß1-42 monomers and fibrils. Eugenitol showed radical scavenging effects and potently reduced the release of proinflammatory cytokines from lipopolysaccharide-treated BV2 cells. Systemic administration of eugenitol blocked Aß aggregate-induced memory impairment in the Morris water maze test in a dose-dependent manner. In 5XFAD mice, prolonged administration of eugenitol ameliorated memory and hippocampal long-term potentiation impairment. Moreover, eugenitol significantly reduced Aß deposits and neuroinflammation in the hippocampus of 5XFAD mice. These results suggest that eugenitol, which has anti-Aß aggregation, Aß fibril dissociation, and anti-inflammatory effects, potently modulates AD-like pathologies in 5XFAD mice, and could be a promising candidate for AD therapy.

Hydrangea macrophylla and Thunberginol C Attenuate Stress-Induced Anxiety in Mice.

Stress is an important neurological input for successful life. However, chronic stress and stress hormones could be a cause of various neurological disorders including anxiety disorders. Therefore, there have been many efforts to find effective materials for curing stress-induced neurological disorders. In this study, we examined the effect of Hydrangea macrophylla (HM) on corticosterone-induced neurotoxicity, stress-induced anxiety in mice and suggested a possible active ingredient of HM. HM protected cortical neurons against neurotoxicity of corticosterone (CORT), a stress hormone. HM also blocked CORT-induced hippocampal synaptic deficit via regulating Akt signaling. Oral administration of HM improved chronic restraint stress-induced anxiety in Elevated Plus maze test along with reduction of plasma corticosterone and TNF-α levels. Moreover, HM reduced stress-induced neuroinflammation and oxidative stress. Thunberginol C, an active ingredient of HM, also prevented CORT-induced neuronal cell death and restraint stress-induced anxiety. Moreover, thunberginol C reduced plasma TNF-α level and neuroinflammation and oxidative stress. Collectively, HM could be a good candidate for preventing stress-induced neurological disorders and thunberginol C may be an active ingredient of HM for this purpose.

Role of extracellular signal-regulated kinase in rubrofusarin-enhanced cognitive functions and neurite outgrowth.

Memory-enhancing agents have long been required for various reasons such as for obtaining a good score in a test in the young and for retaining memory in the aged. Although many studies have found that several natural products may be good candidates for memory enhancement, there is still a need for better agents. The present study investigated whether rubrofusarin, an active ingredient in Cassiae semen, enhances learning and memory in normal mice. Passive avoidance and Morris water maze tests were performed to determine the memory-enhancing ability of rubrofusarin. To investigate synaptic function, hippocampal long-term potentiation (LTP) was measured. Western blotting was performed to determine protein levels. To investigate neurite outgrowth, DCX immunohistochemistry and cell culture were utilised. Rubrofusarin (1, 3, 10, 30 mg/kg) enhanced memory in passive avoidance and Morris water maze tests. Moreover, rubrofusarin ameliorated scopolamine-induced memory impairment. In the rubrofusarin-treated group, high-frequency stimulation induced higher LTP in the hippocampal Schaffer-collateral pathway compared to the control group. The rubrofusarin-treated group showed a higher number of DCX-positive immature neurons with an increase in the length of dendrites compared to the control group in the hippocampal dentate gyrus region. In vitro experiments showed that rubrofusarin facilitated neurite outgrowth in neuro2a cells through extracellular signal-regulated kinase (ERK). Finally, we found that extracellular signal-regulated kinase (ERK) is required for rubrofusarin-induced enhancement of neurite outgrowth, learning and memory. These results demonstrate that rubrofusarin enhances learning and memory and neurite outgrowth, and these might need activation of ERK pathway.

Akt and calcium-permeable AMPA receptor are involved in the effect of pinoresinol on amyloid ß-induced synaptic plasticity and memory deficits.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by memory deficits. Although no drug has given promising results, synaptic dysfunction-modulating agents might be considered potential candidates for alleviating this disorder. Pinoresinol, a lignan found in Forsythia suspensa, is a memory-enhancing agent with excitatory synaptic activation. In the present study, we tested whether pinoresinol reduces learning and memory and excitatory synaptic deficits in an amyloid ß (Aß)-induced AD-like mouse model. Pinoresinol enhanced hippocampal long-term potentiation (LTP) through calcium-permeable AMPA receptor, which was mediated by Akt activation. Moreover, pinoresinol ameliorated LTP deficits in amyloid ß (Aß)-treated hippocampal slices via Akt signaling. Oral administration of pinoresinol ameliorated Aß-induced memory deficits without sensory dysfunction. Moreover, AD-like pathology, including neuroinflammation and synaptic deficit, were ameliorated by pinoresinol administration. Collectively, pinoresinol may be a good candidate for AD therapy by modulating synaptic functions.

REDD1 Is Involved in Amyloid ß-Induced Synaptic Dysfunction and Memory Impairment.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by neurological dysfunction, including memory impairment, attributed to the accumulation of amyloid ß (Aß) in the brain. Although several studies reported possible mechanisms involved in Aß pathology, much remains unknown. Previous findings suggested that a protein regulated in development and DNA damage response 1 (REDD1), a stress-coping regulator, is an Aß-responsive gene involved in Aß cytotoxicity. However, we still do not know how Aß increases the level of REDD1 and whether REDD1 mediates Aß-induced synaptic dysfunction. To elucidate this, we examined the effect of Aß on REDD1-expression using acute hippocampal slices from mice, and the effect of REDD1 short hairpin RNA (shRNA) on Aß-induced synaptic dysfunction. Lastly, we observed the effect of REDD1 shRNA on memory deficit in an AD-like mouse model. Through the experiments, we found that Aß-incubated acute hippocampal slices showed increased REDD1 levels. Moreover, Aß injection into the lateral ventricle increased REDD1 levels in the hippocampus. Anisomycin, but not actinomycin D, blocked Aß-induced increase in REDD1 levels in the acute hippocampal slices, suggesting that Aß may increase REDD1 translation rather than transcription. Aß activated Fyn/ERK/S6 cascade, and inhibitors for Fyn/ERK/S6 or mGluR5 blocked Aß-induced REDD1 upregulation. REDD1 inducer, a transcriptional activator, and Aß blocked synaptic plasticity in the acute hippocampal slices. REDD1 inducer inhibited mTOR/Akt signaling. REDD1 shRNA blocked Aß-induced synaptic deficits. REDD1 shRNA also blocked Aß-induced memory deficits in passive-avoidance and object-recognition tests. Collectively, these results demonstrate that REDD1 participates in Aß pathology and could be a target for AD therapy.

Roles of GABAA receptor α5 subunit on locomotion and working memory in transient forebrain ischemia in mice.

The γ-aminobutyric acid A (GABAA) receptor, which contains a chloride channel, is a typical inhibitory neurotransmitter receptor in the central nervous system. Although the GABAergic neurotransmitter system has been discovered to be involved in various psychological behaviors, such as anxiety, convulsions, and cognitive function, its functional changes under conditions of ischemic pathological situation are still uncovered. In the present study, we attempted to elucidate the functional changes in the GABAergic system after transient forebrain ischemia in mice. A bilateral common carotid artery occlusion for 20 min was used to establish a model of transient forebrain ischemia/reperfusion (tI/R). Delayed treatment with diazepam, a positive allosteric modulator of the GABAA receptor, increased locomotor activity in the open field test and spontaneous alternations in the Y-maze test in tI/R mice, but not in shams. Delayed treatment with diazepam did not alter neuronal death or the number of GABAergic neurons in tI/R mice. However, tI/R induced changes in the protein levels of GABAA receptor subunits in the hippocampus. In particular, the most marked increase in the tI/R group was found in the level of α5 subunit of the GABAA receptor. Similar to delayed treatment with diazepam, delayed treatment with imidazenil, an α5-sensitive benzodiazepine, increased spontaneous alternations in the Y-maze in tI/R mice, whereas zolpidem, an α5-insensitive benzodiazepine, failed to show such effects. These results suggest that tI/R-induced changes in the level of the α5 subunit of the GABAA receptor can alter the function of GABAergic drugs in a mouse model of forebrain ischemia.

Rubrofusarin Attenuates Chronic Restraint Stress-Induced Depressive Symptoms.

The aim of this study was to examine whether rubrofusarin, an active ingredient of the Cassia species, has an antidepressive effect in chronic restraint stress (CRS) mouse model. Although acute treatment using rubrofusarin failed, chronic treatment using rubrofusarin ameliorated CRS-induced depressive symptoms. Rubrofusarin treatment significantly reduced the number of Fluoro-Jade B-positive cells and caspase-3 activation within the hippocampus of CRS-treated mice. Moreover, rubrofusarin treatment significantly increased the number of newborn neurons in the hippocampus of CRS-treated mice. CRS induced activation of glycogen synthase kinase-3ß and regulated development and DNA damage responses, and reductions in the extracellular-signal-regulated kinase pathway activity were also reversed by rubrofusarin treatment. Microglial activation and inflammasome markers, including nod-like receptor family pyrin domain containing 3 and adaptor protein apoptosis-associated speck-like protein containing CARD, which were induced by CRS, were ameliorated by rubrofusarin. Synaptic plasticity dysfunction within the hippocampus was also rescued by rubrofusarin treatment. Within in vitro experiments, rubrofusarin blocked corticosterone-induced long-term potentiation impairments. These were blocked by LY294002, which is an Akt inhibitor. Finally, we found that the antidepressant effects of rubrofusarin were blocked by an intracerebroventricular injection of LY294002. These results suggest that rubrofusarin ameliorated CRS-induced depressive symptoms through PI3K/Akt signaling.

The effect of maslinic acid on cognitive dysfunction induced by cholinergic blockade in mice.

BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is the most prevalent disease associated with cognitive dysfunction. Current AD therapeutic agents have several gastrointestinal or psychological adverse effects and therefore, novel therapeutic agents with fewer adverse effects must be developed. Previously, we demonstrated that oleanolic acid, which is similar in chemical structure to maslinic acid, ameliorates cognitive impairment through the activation of tropomyosin receptor kinase (TrkB)-ERK-cAMP response element-binding protein (CREB) phosphorylation and increased levels of brain-derived neurotrophic factor (BDNF). In the present study, we investigate the effect of maslinic acid on cholinergic blockade-induced memory impairment in mice. METHODS AND KEY RESULTS: Maslinic acid reversed scopolamine-induced memory impairment, as determined by the Y-maze, passive avoidance and Morris water maze tests. In addition, we also observed that ERK-CREB, PI3K and PKB (Akt) phosphorylation levels were increased by maslinic acid administration in the mouse hippocampus. Moreover, we determined that the effects of maslinic acid on scopolamine-induced memory impairment in the passive avoidance test were abolished by a specific TrkB receptor antagonist (ANA-12). Additionally, we observed similar temporal changes in the expression levels between BDNF and tissue plasminogen activator in the hippocampus. CONCLUSION AND IMPLICATIONS: These findings suggest that maslinic acid enhances cognitive function through the activation of BDNF and its downstream pathway signalling in the hippocampus and that it might be a potential therapeutic agent for cognitive decline, such as that observed in AD.

ß-Amyrin Ameliorates Alzheimer's Disease-Like Aberrant Synaptic Plasticity in the Mouse Hippocampus.

Alzheimer's disease (AD) is a progressive and most frequently diagnosed neurodegenerative disorder. However, there is still no drug preventing the progress of this disorder. ß-Amyrin, an ingredient of the surface wax of tomato fruit and dandelion coffee, is previously reported to ameliorate memory impairment induced by cholinergic dysfunction. Therefore, we tested whether ß-amyrin can prevent AD-like pathology. ß-Amyrin blocked amyloid ß (Aß)-induced long-term potentiation (LTP) impairment in the hippocampal slices. Moreover, ß-amyrin improved Aß-induced suppression of phosphatidylinositol-3-kinase (PI3K)/Akt signaling. LY294002, a PI3K inhibitor, blocked the effect of ß-amyrin on Aß-induced LTP impairment. In in vivo experiments, we observed that ß-amyrin ameliorated object recognition memory deficit in Aß-injected AD mice model. Moreover, neurogenesis impairments induced by Aß was improved by ß-amyrin treatment. Taken together, ß-amyrin might be a good candidate of treatment or supplement for AD patients.

Cryptotanshinone enhances neurite outgrowth and memory via extracellular signal-regulated kinase 1/2 signaling.

Neurite outgrowth is important process in synaptic formation and neuronal development. Many previous studies reported that natural compounds as well as neurotrophins induce neurite outgrowth through various signaling pathways. In this study, we tested the effect of cryptotanshinone (CPT), a constituent of Salvia miltiorrhiza Bunge, on neurite outgrowth using neuro2a cell line, a mouse neuroblastoma cell line. And then, we examined the effect of CPT on learning and memory. We first found that CPT facilitated neurite outgrowth in a concentration-dependent manner. Although CPT induced MTT reduction, CPT did not induce LDH release. Moreover, CPT suppressed cell proliferation. CPT increased ERK1/2 phosphorylation and ERK1/2 inhibitor blocked CPT-facilitated neurite outgrowth. CPT also enhanced learning and memory without affecting basal sensory conditions and increased ERK1/2 phosphorylation in the hippocampus in a dose-dependent manner. These results demonstrate that CPT facilitates neurite outgrowth and enhances learning and memory, which may be mediated by facilitating ERK1/2 signal.

Spinosin Attenuates Alzheimer's Disease-Associated Synaptic Dysfunction via Regulation of Plasmin Activity.

Hippocampal synaptic dysfunction is a hallmark of Alzheimer's disease (AD). Many agents regulating hippocampal synaptic plasticity show an ameliorative effect on AD pathology, making them potential candidates for AD therapy. In the present study, we investigated spinosin as a regulating agent of synaptic plasticity in AD. Spinosin attenuated amyloid ß (Aß)-induced long-term potentiation (LTP) impairment, and improved plasmin activity and protein level in the hippocampi of 5XFAD mice, a transgenic AD mouse model. Moreover, the effect of spinosin on hippocampal LTP in 5XFAD mice was prevented by 6-aminocaproic acid, a plasmin inhibitor. These results suggest that spinosin improves synaptic function in the AD hippocampus by regulating plasmin activity.

The effect of coniferaldehyde on neurite outgrowth in neuroblastoma Neuro2a cells.

Neurite outgrowth is the differentiation process by which neurons establish synapses. In the dentate gyrus of the hippocampus, new neurons are constantly produced and undergo neurite outgrowth to form synapses, and this process is involved in cognitive ability. Therefore, if an agent could modulate neurite outgrowth, it could potentially be developed as a compound for modulating cognitive ability. In this study, we examined whether coniferaldehyde, a natural compound, regulates neurite outgrowth in Neuro2a cells. We ascertained morphological changes and measured the percentage of neurite-bearing cells and neurite lengths. Coniferaldehyde significantly increased the percentage of neurite-bearing cells, and the length of neurites in a concentration-dependent manner, without inducing cell death. We then have identified that, coniferaldehyde activates the extracellular signals-regulated Kinase 1 and 2 (ERK1/2), and further noted that, U0126, an ERK1/2 inhibitor, blocks coniferaldehyde-facilitated neurite outgrowth. Moreover, Subchronic administration of CA enhanced learning and memory, and increased neurite length of newborn neurons in the hippocampus. These results suggest that coniferaldehyde induces neurite outgrowth by a process possibly mediated by ERK1/2 signaling and enhances learning and memory.

Rubrofusarin inhibits Aß aggregation and ameliorates memory loss in an Aß-induced Alzheimer's disease-like mouse model.

The misfolding and aggregation of amyloid ß (Aß) peptide is a common histopathologic characteristic in patients with Alzheimer's disease, so is considered to play an critical role. In the present study, we examined the effect of rubrofusarin, an ingredient of Cassiae semen, on Aß aggregation and memory loss in an AD mouse model. Rubrofusarin inhibited Aß aggregation in a concentration-dependent manner. Moreover, rubrofusarin dis-aggregated preformed Aß fibrils in a concentration-dependent manner. Although aggregated Aß induced memory loss, Aß pre-incubated with rubrofusarin failed to induce memory loss. Moreover, rubrofusarin administration ameliorated Aß aggregates-induced memory loss. Finally, rubrofusarin reduced glial fibrillary acidic protein or Iba-1-positive area, markers of neuroinflammation, in the hippocampus of Aß-treated mice. These results suggest that rubrofusarin can decrease Aß fibril formation and ameliorate memory loss in the AD mouse model.

The fruit of Crataegus pinnatifida ameliorates memory deficits in ß-amyloid protein-induced Alzheimer's disease mouse model.

ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Crataegus pinnatifida is a traditional medicine widely used as digestive drug in East Asia. Although Chinese herbal medicine used it for mental health, scientific evidence does not exist, yet. AIMS OF STUDY: The aim of this study is to show that the ethanol extract of the fruit of Crataegus pinnatifida (CPE) has neuroprotective effect on Alzheimer' disease model mice. MATERIALS AND METHODS: Intracerebroventricular injection of Aß was used to induce Alzheimer's disease-like pathology. Passive avoidance and Y-maze tasks were used to examine the effect of CPE on memory impairments by Aß. Immunohistochemistry was used to examine the effect of CPE on glial activation. ThT assay was used to observe the effect of CPE on Aß aggregation. MTT and LDH release assays were utilized to examine effects of CPE on Aß-induced cytotoxicity. RESULTS: CPE prevented memory deficit in Aß-induced memory impairment model. Moreover, CPE prevented glial activation in the hippocampus of Aß-injected model. In in vitro test, CPE inhibited Aß fibril formation in a concentration-dependent manner. CPE also caused disaggregation of Aß fibrils. Along with this, CPE blocked neuronal cell death induced by Aß. CONCLUSIONS: Collectively, these experimental findings demonstrated that CPE could be a candidate for development of AD therapy.

The effects of pinoresinol on cholinergic dysfunction-induced memory impairments and synaptic plasticity in mice.

Dementia is a category of brain diseases that cause a decrease in cognitive functions. Alzheimer's disease (AD) is the most frequently mentioned neurodegenerative disease showing dementia. Although many useful drugs for dementia were developed, we still need better and safer drugs. Here, we tested pinoresinol, a lignan found in sesame seed and olive oil, whether it could be a candidate for this purpose. Pinoresinol (25 mg/kg, p.o.) ameliorated memory impairment in dementia model induced by cholinergic blockade in the passive avoidance test in a dose-dependent manner. Moreover, pinoresinol (50 µM) facilitated induction of hippocampal long-term potentiation, a cellular model of learning and memory. Pinoresinol blocked acetylcholinesterase (AchE), an acetylcholine-degrading enzyme, activity in a concentration-dependent manner. Moreover, pinoresinol (50 µM) facilitated calcium influx into neuro2a cell. These results suggest that pinoresinol improves memory impairment and facilitates hippocampal LTP induction and these results might be related to the effect of pinoresinol on AChE and calcium influx.

The ethanol extract of Zizyphus jujuba var. spinosa seeds ameliorates the memory deficits in Alzheimer's disease model mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Zizyphus jujuba var. spinosa (Bunge) Hu ex H.F. Chow (Rhamnaceae) have long been treated as hypnotic agent for sleep disturbances in traditional Chinese and Korean medicine and many previous studies have focused on its effect in central nervous system. AIMS OF STUDY: The present study aimed to provide evidence showing that the ethanol extract of Zizyphus jujuba var. spinosa seeds (EEZS), which may regulate plasmin activity, has the potential to serve as a therapeutic agent for AD. MATERIALS AND METHODS: Synaptic function was determined by measuring long-term potentiation (LTP) in Shaffer-collateral pathway of the hippocampus. Protein levels of plasmin or plasminogen were examined using western blotting. Plasmin activity was measured using ELISA. Cognitive functions were measured using passive avoidance and object recognition tests in the 5XFAD mice. RESULTS: Our in vitro analysis revealed that EEZS-treated hippocampal slices from 5XFAD mice, a mouse model of AD, showed significantly higher long-term potentiation levels than did vehicle-treated hippocampal slices from 5XFAD mice (P < 0.05). Additionally, EEZS significantly elevated the plasmin level and activity in the hippocampal slices from 5XFAD mice (P < 0.05). Co-treating the slices with EEZS and 6-aminocaproic acid, a plasmin inhibitor, blocked the ameliorating effects of EEZS on the synaptic deficits that were present in 5XFAD mice. Compatible with the in vitro study, the results of our in vivo investigation showed that administering EEZS orally to 5XFAD mice ameliorated their memory impairments. Orally administered EEZS also elevated the plasmin level and activity in the hippocampus of 5XFAD mice. CONCLUSIONS: Collectively, our findings suggest that EEZS alleviates the AD-like symptoms in 5XFAD mice by regulating of plasmin activity and EEZS may be a suitable treatment for AD.