Intracerebroventricular Injection Of Aβ1-42 Research Articles

Cornuside ameliorates cognitive impairments via RAGE/TXNIP/NF-κB signaling in Aβ1-42 induced Alzheimer's disease mice.

Cornuside has been discovered to improve learning and memory in AD mice, however, its underlying mechanism was not fully understood. In the present study, we established an AD mice model by intracerebroventricular injection of Aβ1-42, which were treated with cornuside (3, 10, 30mg/kg) for 2weeks. Cornuside significantly ameliorated cognitive function of AD mice in series of behavioral tests, including Morris water maze test, nest building test, novel object recognition test and step-down test. Additionally, cornuside could attenuate neuronal injury, and promote cholinergic synaptic transmission by restoring the level of acetylcholine (ACh) via inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as facilitating choline acetyltransferase (ChAT). Furthermore, cornuside inhibited oxidative stress levels amplified as decreased malondialdehyde (MDA), by inhibiting TXNIP expression, improving total anti-oxidative capacity (TAOC), raising activities of superoxide dismutase (SOD) and catalase (CAT). Cornuside also reduced the activation of microglia and astrocytes, decreased the level of proinflammatory factors TNF-α, IL-6, IL-1β, iNOS and COX2 via interfering RAGE-mediated IKK-IκB-NF-κB phosphorylation. Similar anti-oxidative and anti-inflammatory effects were also found in LPS-stimulated BV2 cells via hampering RAGE-mediated TXNIP activation and NF-κB nuclear translocation. Virtual docking revealed that cornuside could interact with the active pocket of RAGE V domain directly. In conclusion, cornuside could bind to the RAGE directly impeding the interaction of Aβ and RAGE, and cut down the expression of TXNIP inhibiting ROS production and oxidative stress, as well as hamper NF-κB p65 mediated the inflammation.

Blockage of metallothionein synthesis via adrenaline β receptor activation invalidates dehydroeffusol-mediated prevention of amyloid β1-42 toxicity

Dehydroeffusol, a major phenanthrene in Juncus effusus, protects neurodegeneration induced by intracellular Zn2+ ferried by extracellular amyloid β1-42 (Aβ1-42). Here we focused on adrenaline β receptor activation and the induction of metallothioneins (MTs), intracellular Zn2+-binding proteins to test the protective mechanism of dehydroeffusol. Isoproterenol, an agonist of adrenergic β receptors elevated the level of MTs in the dentate granule cell layer 1 day after intracerebroventricular (ICV) injection. When Aβ1-42 was injected 1 day after isoproterenol injection, pre-injection of isoproterenol protected Aβ1-42 toxicity via reducing the increase in intracellular Zn2+ after ICV injection of Aβ1-42. On the basis of the effect of increased MTs by isoproterenol, dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 2 days. On day later, dehydroeffusol elevated the level of MTs and prevented Aβ1-42 toxicity via reducing Aβ1-42-mediated increase in intracellular Zn2+. In contrast, propranolol, an antagonist of adrenergic β receptors reduced the level of MTs increased by dehydroeffusol, resulting in invalidating the preventive effect of dehydroeffusol on Aβ1-42 toxicity. The present study indicates that blockage of MT synthesis via adrenaline β receptor activation invalidates dehydroeffusol-mediated prevention of Aβ1-42 toxicity. It is likely that MT synthesis via adrenaline β receptor activation is beneficial to neuroprotection and that oral intake of dehydroeffusol preventively serves against the Aβ1-42 toxicity.

Inhibition of NMDA Receptor Activation in the Rostral Ventrolateral Medulla by Amyloid-β Peptide in Rats.

N-methyl-D-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are important in regulating sympathetic tone and cardiovascular function in the rostral ventrolateral medulla (RVLM). Amyloid-beta peptide (Aβ) is linked to the pathogenesis of Alzheimer's disease (AD). Cerebro- and cardiovascular diseases might be the risk factors for developing AD. The present study examines the acute effects of soluble Aβ on the function of NMDA receptors in rats RVLM. We used the magnitude of increases in the blood pressure (pressor responses) induced by microinjection of NMDA into the RVLM as an index of NMDA receptor function in the RVLM. Soluble Aβ was applied by intracerebroventricular (ICV) injection. Aβ1-40 at a lower dose (0.2 nmol) caused a slight reduction, and a higher dose (2 nmol) showed a significant decrease in NMDA-induced pressor responses 10 min after administration. ICV injection of Aβ1-42 (2 nmol) did not affect NMDA-induced pressor responses in the RVLM. Co-administration of Aβ1-40 with ifenprodil or memantine blocked the inhibitory effects of Aβ1-40. Immunohistochemistry analysis showed a significant increase in the immunoreactivity of phosphoserine 1480 of GluN2B subunits (pGluN2B-serine1480) in the neuron of the RVLM without significant changes in phosphoserine 896 of GluN1 subunits (pGluN1-serine896), GluN1 and GluN2B, 10 min following Aβ1-40 administration compared with saline. Interestingly, we found a much higher level of Aβ1-40 compared to that of Aβ1-42 in the cerebrospinal fluid (CSF) measured using enzyme-linked immunosorbent assay 10 min following ICV administration of the same dose (2 nmol) of the peptides. In conclusion, the results suggest that ICV Aβ1-40, but not Aβ1-42, produced an inhibitory effect on NMDA receptor function in the RVLM, which might result from changes in pGluN2B-serine1480 (regulated by casein kinase II). The different elimination of the peptides in the CSF might contribute to the differential effects of Aβ1-40 and Aβ1-42 on NMDA receptor function.

Deleterious and protective effects of epothilone-D alone and in the context of amyloid β- and tau-induced alterations.

Amyloid-β (Aβ) and hyperphosphorylated tau (P-tau) are Alzheimer's disease (AD) biomarkers that interact in a complex manner to induce most of the cognitive and brain alterations observed in this disease. Since the neuronal cytoskeleton is a common downstream pathological target of tau and Aβ, which mostly lead to augmented microtubule instability, the administration of microtubule stabilizing agents (MSAs) can protect against their pathological actions. However, the effectiveness of MSAs is still uncertain due to their state-dependent negative effects; thus, evaluating their specific actions in different pathological or physiological conditions is required. We evaluated whether epothilone-D (Epo-D), a clinically used MSA, rescues from the functional and behavioral alterations produced by intracerebroventricular injection of Aβ, the presence of P-tau, or their combination in rTg4510 mice. We also explored the side effects of Epo-D. To do so, we evaluated hippocampal-dependent spatial memory with the Hebb-Williams maze, hippocampal CA1 integrity and the intrinsic and synaptic properties of CA1 pyramidal neurons with the patch-clamp technique. Aβ and P-tau mildly impaired memory retrieval, but produced contrasting effects on intrinsic excitability. When Aβ and P-tau were combined, the alterations in excitability and spatial reversal learning (i.e., cognitive flexibility) were exacerbated. Interestingly, Epo-D prevented most of the impairments induced Aβ and P-tau alone and combined. However, Epo-D also exhibited some side effects depending on the prevailing pathological or physiological condition, which should be considered in future preclinical and translational studies. Although we did not perform extensive histopathological evaluations or measured microtubule stability, our findings show that MSAs can rescue the consequences of AD-like conditions but otherwise be harmful if administered at a prodromal stage of the disease.

Neuroprotective effects of vinpocetine, as a phosphodiesterase 1 inhibitor, on long-term potentiation in a rat model of Alzheimer’s disease

BackgroundVinpocetine (Vin) is known as a phosphodiesterase 1 inhibitor (PDE1-I) drug with multilateral effects, including antioxidant and anti-inflammatory activity. In this research, we investigated the neuroprotective and therapeutic effects of Vin through hippocampal synaptic plasticity on a rat’s model of Alzheimer’s disease (AD) induced by an intracerebroventricular (ICV) injection of beta-amyloid (Aβ).MethodsSixty adult male Wistar rats were randomly divided into six groups: 1. control, 2. sham, 3. Aβ, 4. pretreatment (Vin + Aβ): Vin (4 mg/kg, gavage) for 30 days and then, inducing an AD model by an ICV injection of Aβ(1–42), 5. treatment (Aβ + Vin): inducing an AD model and then receiving Vin for 30 days by gavage, and 7. pretreatment + treatment (Vin + Aβ + Vin): receiving Vin by gavage for 30 days before and 30 days after the induction of an AD model. After these procedures, via stereotaxic surgery, the stimulating electrodes were placed at the perforant pathway (PP) and the recording electrodes were implanted in the dentate gyrus.ResultsExcitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the Aβ group meaningfully diminished compared to the control group after the induction of long-term potentiation (LTP).ConclusionsVin could significantly prevent the Aβ effects on LTP. It can be concluded that pretreatment and treatment with Vin can be neuroprotective against harmful consequences of Aβ on hippocampal synaptic plasticity.

The Protective Effects of Policosanol on Learning and Memory Impairments in a Male Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD), the most common form of dementia, is characterized by a progressive decline in cognitive performance and memory formation. The present study was designed to investigate the effect of policosanol (PCO) on cognitive function, oxidative-antioxidative status, and amyloid-beta (Aβ) plaque formation in an AD rat model induced by intracerebroventricular (ICV) injection of Aβ1-40. Healthy adult male Wistar rats were randomly divided into seven groups: control, sham (5 μL, ICV injection of phosphate-buffered saline), AD model (5 μL, ICV injection of Aβ), acacia gum (50mg/kg, 8weeks, gavage), PCO (50mg/kg, 8weeks, gavage), AD + acacia gum (50mg/kg, 8weeks, gavage), and AD + PCO (50mg/kg, 8weeks, gavage). During the ninth and tenth weeks of the study, the cognitive function of the rats was assessed by commonly used behavioral paradigms. Subsequently, oxidative-antioxidative status was examined in the serum. Moreover, compact Aβ plaques were detected by Congo red staining. The results showed that injection of Aβ impaired recognition memory in the novel object recognition test, reduced the spatial cognitive ability in the Morris water maze, and alleviated retention and recall capability in the passive avoidance task. Additionally, injection of Aβ resulted in increased total oxidant status, decreased total antioxidant capacity, and enhanced Aβ plaque formation in the rats. Intriguingly, PCO treatment improved all the above-mentioned neuropathological changes in the Aβ-induced AD rats. The results suggest that PCO improves Aβ-induced cognitive decline, possibly through modulation of oxidative-antioxidative status and inhibition of Aβ plaque formation.

Orally Bioavailable Prodrugs of ψ-GSH: A Potential Treatment for Alzheimer's Disease.

Addressing glycation-induced oxidative stress in Alzheimer's disease (AD) is an emerging pharmacotherapeutic strategy. Restoration of the brain glyoxalase enzyme system that neutralizes reactive dicarbonyls is one such approach. Toward this end, we designed, synthesized, and evaluated a γ-glutamyl transpeptidase-resistant glyoxalase substrate, ψ-GSH. Although mechanistically successful, the oral efficacy of ψ-GSH appeared as an area in need of improvement. Herein, we describe our rationale for the creation of prodrugs that mask the labile sulfhydryl group. In vitro and in vivo stability studies identified promising prodrugs that could deliver pharmacologically relevant brain levels of ψ-GSH. When administered orally to a mouse model generated by the intracerebroventricular injection of Aβ1-42, the compounds conferred cognitive benefits. Biochemical and histological examination confirmed their effects on neuroinflammation and oxidative stress. Collectively, we have identified orally efficacious prodrugs of ψ-GSH that are able to restore brain glyoxalase activity and mitigate inflammatory and oxidative pathology associated with AD.

The Effect of 40-Hz White LED Therapy on Structure-Function of Brain Mitochondrial ATP-Sensitive Ca-Activated Large-Conductance Potassium Channel in Amyloid Beta Toxicity.

Photobiomodulation therapy has become the focus of medical research in many areas such as Alzheimer's disease (AD), because of its modulatory effect on cellular processes through light energy absorption via photoreceptors/chromophores located in the mitochondria. However, there are still many questions around the underlying mechanisms. This study was carried out to unravel whether the function-structure of ATP-sensitive mitoBKCa channels, as crucial components for maintenance of mitochondrial homeostasis, can be altered subsequent to light therapy in AD. Induction of Aβ neurotoxicity in male Wistar rats was done by intracerebroventricular injection of Aβ1-42. After a week, light-treated rats were exposed to 40-Hz white light LEDs, 15min for 7days. Electrophysiological properties of mitoBKCa channel were investigated using a channel incorporated into the bilayer lipid membrane, and mitoBKCa-β2 subunit expression was determined using western blot analysis in Aβ-induced toxicity and light-treated rats. Our results describe that conductance and open probability (Po) of mitoBKCa channel decreased significantly and was accompanied by a Po curve rightward shift in mitochondrial preparation in Aβ-induced toxicity rats. We also showed a significant reduction in expression of mitoBKCa-β2 subunit, which is partly responsible for a leftward shift in BKCa Po curve in low calcium status. Interestingly, we provided evidence of a significant improvement in channel conductance and Po after light therapy. We also found that light therapy improved mitoBKCa-β2 subunit expression, increasing it close to saline group. The current study explains a light therapy improvement in brain mitoBKCa channel function in the Aβ-induced neurotoxicity rat model, an effect that can be linked to increased expression of β2 subunit.

Effects of Naodesheng tablets on amyloid beta-induced dysfunction: A traditional Chinese herbal formula with novel therapeutic potential in Alzheimer's disease revealed by systems pharmacology

Naodesheng (NDS) tablets have been widely used to treat ischemic stroke clinically. NDS relieves neurological function impairment and improve learning and memory in rats with focal cerebral ischemia, suggesting that NDS has potential for Alzheimer’s disease (AD) treatment. However, there are no studies about its effective material basis and possible mechanisms. In this study, a systems pharmacology method was applied to reveal the potential molecular mechanism of NDS in the treatment of AD. First, we obtained 360 NDS candidate constituents through ADMET filter analysis. Then, 115 AD‐related targets were uncovered by pharmacophore model prediction via mapping the predicted targets against AD-related proteins. In addition, compound-target and target-function networks were established to suggest potential synergistic effects among the candidate constituents. Furthermore, potential targets regulated by NDS were integrated into AD-related pathways to demonstrate the therapeutic mechanism of NDS in AD treatment. Subsequently, a validation experiment proved the therapeutic effect of NDS on cognitive dysfunction in rats with intracerebroventricular injection of Aβ. We found that administration of NDS tablets regulates β-amyloid metabolism, improves synaptic plasticity, inhibits neuroinflammation and improves learning and memory function. In conclusion, this is the first study to provide a comprehensive systems pharmacology approach to elucidate the potential therapeutic mechanism of NDS tablets for AD treatment. We suggest that the protective effects of NDS in neurodegenerative conditions could be partly attributed to its role in improving synaptic plasticity and inhibiting neuroinflammation via NF-κB signaling pathway inhibition and cAMP/PKA/CREB signaling pathway activation.

Quercetin-3-O-Glucuronide Alleviates Cognitive Deficit and Toxicity in Aβ1-42 -Induced AD-Like Mice and SH-SY5Y Cells.

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) related imbalance, Tau-hyperphosphorylation, and neuroinflammation, in which Aβ and neuroinflammation can induce brain insulin resistance (IR). Gut microbiome disorder is correlated with inflammation in AD. As of yet, there are no effective treatments clinically. Thus, it is focused on the potential benefit of quercetin-3-O-glucuronide (Q3G), a pharmacologically active flavonol glucuronide, on AD treatment by regulating brain IR and the gut microbiome. AD mice model built through intracerebroventricular injection of Aβ1-42 and AD cell model developed through the SH-SY5Y cell line and Aβ1-42 are used to explore the protective effects of Q3G on AD. Neurobehavioral test, brain insulin signaling pathway, and high-throughput pyrosequencing of 16S rRNA are assessed. Data show that Q3G attenuates neuroinflammation and brain IR in Aβ1-42 -injected mice and relieves apoptosis in Aβ1-42 -treated SH-SY5Y cells by interrupting the downstream insulin signaling. Q3G ameliorates Aβ accumulation and Tau phosphorylation, restores CREB and BDNF levels in the hippocampus , and reverses Aβ1-42 -induced cognitive impairment. Besides, Q3G restores Aβ1-42 -induced reduction of short-chain fatty acids (SCFAs) and gut microbiota dysbiosis. Q3G can alleviate brain IR through directly acting on the brain or modulating the gut-brain axis, ultimately to relieve Aβ1-42 -induced cognitive dysfunction.

The flavonoids of okra insulates against oxidative stress, neuroinflammation and restores BDNF levels in Aβ1–42 induced mouse model of Alzheimer's disease

Okra (Abelmoschus esculentus [L.] Moench.) has been used as a natural drug in East or West Africa for many centuries, as well as consumed in most areas of the world as a tropical vegetable. The study aimed to evaluate whether the flavonoids of okra fruit (FOF) administration influence Aβ1-42-induced learning and memory impairment, and explore the underlying mechanisms. The Y-maze task and the Morris water maze test were used for evaluating cognition processes. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), and glutathione peroxidase (GSH-Px) were detected by ELISA kits. The expressions of nuclear factor kappa-light chain-enhancer of activated B (NF-κB), brain-derived neurotrophic factor (BDNF), cAMP-response element-binding protein (CREB), extracellular signal-regulated kinase (ERK), phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT), glycogen synthase kinase-3β (GSK-3β) were studied by western blot. Histopathological changes were observed by H.E. straining. The results showed that intracerebroventricular injection of Aβ1-42 was effective in producing memory deficits in mice. Besides, Aβ1-42 exposure could significantly increase the levels of NF-κB, TNF-α, IL-1β, and decreased T-AOC, the activities of SOD and GSH-Px in the hippocampus and cortex. Furthermore, the level of BDNF was also reduced, accompanied by down-regulated CREB/ERK and PI3K/AKT/GSK-3β signaling pathways in the hippocampus and cortex. Nevertheless, chronic administration of FOF (100 or 300mg/kg, i.g.) significantly prevented Aβ1-42-induced behavioral and biochemical alterations. It also suggested that FOF could improve the cognitive deficits in AD-like model mice, which might be mediated by regulation of BDNF levels in cortex and hippocampus and up-regulating of CREB/ERK and PI3K/AKT/GSK3β pathways, as well as alleviation of oxidative stress and neuroinflammation.

Caterpillar Medicinal Mushroom, Cordyceps militaris (Ascomycota), Attenuates Aβ1-42-Induced Amyloidogenesis and Inflammatory Response by Suppressing Amyloid Precursor Protein Progression and p38 MAPK/JNK Activation.

The deposition of amyloid beta (Aβ) is a neuropathological feature of Alzheimer's disease (AD). Cordyceps militaris is an edible medicinal fungus in Asian countries with antioxidative, antiaging, antitumor, and immunomodulatory effects. In this study, we investigated the neuroprotective mechanisms of C. militaris in the brain of Aβ1-42-injected AD mice. An intracerebroventricular injection of Aβ1-42 (total 3 µg/mouse) resulted in neurological damage, including amyloidogenesis and neuroinflammation; however, C. militaris attenuated Aβ1-42-induced amyloidogenesis and inflammatory responses. Oral administration of C. militaris at concentrations of 100 and 200 mg/kg suppressed acetylcholinesterase activity. In addition, C. militaris treatment downregulated amyloid precursor protein levels, with a decrease in β-secretase activity. Moreover, C. militaris significantly enhanced the expression of brain-derived neurotrophic factor. Furthermore, C. militaris-administered groups had inactivated inflammatory responses by downregulation of inducible nitric oxide synthase and cyclooxygenase-2 protein expression. The injection of Aβ1-42 resulted in the activation of p38 MAPK and c-Jun N-terminal kinase, which was rescued by C. militaris. These results suggest that C. militaris has a protective effect against Aβ1-42-induced neurological damage.

Oligomer β-amyloid Induces Hyperactivation of Ras to Impede NMDA Receptor-Dependent Long-Term Potentiation in Hippocampal CA1 of Mice.

The activity of Ras, a small GTPase protein, is increased in brains with Alzheimer’s disease. The objective of this study was to determine the influence of oligomeric Aβ1-42 on the activation of Ras, and the involvement of the Ras hyperactivity in Aβ1-42-induced deficits in spatial cognition and hippocampal synaptic plasticity. Herein, we show that intracerebroventricular injection of Aβ1-42 in mice (Aβ-mice) enhanced hippocampal Ras activation and expression, while 60 min incubation of hippocampal slices in Aβ1-42 (Aβ-slices) only elevated Ras activity. Aβ-mice showed deficits in spatial cognition and NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) in hippocampal CA1, but basal synaptic transmission was enhanced. The above effects of Aβ1-42 were corrected by the Ras inhibitor farnesylthiosalicylic acid (FTS). ERK2 phosphorylation increased, and Src phosphorylation decreased in Aβ-mice and Aβ1-42-slices. Both were corrected by FTS. In CA1 pyramidal cells of Aβ1-42-slices, the response of AMPA receptor and phosphorylation of GluR1 were enhanced with dependence on Ras activation rather than ERK signaling. In contrast, NMDA receptor (NMDAR) function and GluN2A/2B phosphorylation were downregulated in Aβ1-42-slices, which was recovered by application of FTS or the Src activator ouabain, and mimicked in control slices treated with the Src inhibitor PP2. The administration of PP2 impaired the spatial cognition and LTP induction in control mice and FTS-treated Aβ-mice. The treatment of Aβ-mice with ouabain rescued Aβ-impaired spatial cognition and LTP. Overall, the results indicate that the oligomeric Aβ1-42 hyperactivates Ras and thereby causes the downregulation of Src which impedes NMDAR-dependent LTP induction resulting in cognitive deficits.

β-Asarone improves learning and memory in Aβ1-42-induced Alzheimer's disease rats by regulating PINK1-Parkin-mediated mitophagy.

Alzheimer's disease (AD) is a chronic neurodegenerative disease that is characterized by the extracellular accumulation of β-amyloid (Aβ). Many studies have shown a close relationship between autophagy and the formation of Aβ. As AD develops and progresses, mitophagy diminishes insoluble Aβ, and mitochondrial dysfunction seems to be a determining factor in the pathogenesis of AD. In our previous study, we showed that β-asarone pharmacological effects in APP/PS1 transgenic mice, reducing Aβ expression. However, the specific mechanism of this effect remains unclear. In this study, AD model rats induced by intracerebroventricular injection of Aβ1-42 were randomly divided into nine groups, and medical intervention was applied to the animals for 30days. Subsequently, spatial learning and memory were evaluated by the water maze test. Bcl-2 levels in the hippocampus were determined by western blotting (WB). The protein expression of Aβ1-42, Beclin-1, p62, PINK1, and Parkin was assessed by WB and immunohistochemistry (IHC). The data showed that after β-asarone treatment, the learning and memory of the AD rats were clearly improved compared with those of the model group. Moreover, β-asarone decreased Aβ1-42, Bcl-2, and p62 levels but increased Beclin-1 levels compared with those in the model group. In addition, we treated a group of rats with CsA to inhibit mitophagy. β-Asarone increased PINK1 and Parkin expression compared with that in the model group. The results showed that β-asarone can improve the learning and memory of rats with Aβ1-42-induced AD by effectively promoting PINK1-Parkin-mediated mitophagy. Taken together, these results suggest that β-asarone may have the capacity to become a pharmaceutical agent for the treatment of AD in the future.

β-Lapachone attenuates cognitive impairment and neuroinflammation in beta-amyloid induced mouse model of Alzheimer's disease

Oxidative stress and neuroinflammation are critically involved in amyloid beta (Aβ) induced cognitive impairments. β-Lapachone (β-LAP) is a natural activator of NAD(P)H quinone oxidoreductase 1 (NQO1) which has antioxidant and anti-inflammatory properties.This study investigated the effect of β-LAP administration on Aβ-induced memory deficit, oxidative stress, neuroinflammation, and apoptosis cell death in the hippocampus. Forty BALB/c mice were allocated into control, sham, β-LAP (βL), Aβ, and Aβ + βL groups. Intracerebroventricular injection of Aβ1-42 was used to induce Alzheimer’s disease (AD) model. Mice in the βL and Aβ + βL groups were treated with β-LAP (10 mg/kg, i.p) for 4 days. Results revealed that β-LAP attenuated memory impairment in the Aβ-received mice, as measured in the novel object recognition (NOR) and Barnes maze tests. Moreover, Aβ resulted in inflammasome activation evident by enhanced caspase-1 immunoreactivity and interleukin-1 beta (IL-1β) protein levels. However, β-LAP could markedly reduce reactive oxygen species (ROS) production and down-regulate mRNA expression of NLRP3 inflammasome and protein levels of cleaved caspase 1 and IL-1β. Additionally, β-LAP-treated mice showed increased SIRT1 levels and NAD+/NADH ratio in the hippocampus. These results were followed by fewer number of TUNEL-positive cell, reduced hippocampal atrophy and neuronal loss in the hippocampal dentate gyrus (DG). These results indicated that the protective effect of β-LAP against AD-associated cognitive deficits is partially through its strong antioxidant and anti-inflammatory actions.

Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer's Disease.

BackgroundAlzheimer’s disease (AD), a leading cause of dementia, becomes a serious health issue for individuals and society around the world. AD is a neurodegenerative disease characterized by the deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles (NFT) and the loss of large numbers of neurons. To date, there is no effective treatment for AD, and thus, to enhance neurogenesis in the AD brain may be a therapeutic strategy. RAS signaling pathway involves in synaptic plasticity and memory formation, which is overexpressed in brains with AD. This study used Aβ1-42-injected mice (Aβ1-42-mice) as the AD model to investigate the effects of S-trans, trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, on the impairment of neurogenesis and the spatial cognitive deficits.Materials and methodsAD model mice were manufactured through intracerebroventricular injection of Aβ1-42. Morris water maze (MWM) was performed to evaluate the capacity of spatial memory, and Nissl staining was applied to assess neuronal damage in the hippocampus CA1. Immunohistochemistry of 5-bromo-2-deoxyuridine (BrdU), BrdU/neuronal nuclei (NeuN), and doublecortin (DCX) were used to detect progenitor cell proliferation, maturation, and neurite growth, respectively. And the expression levels of RAS, ERK/ERK phosphorylation (p-ERK) and CREB/CREB phosphorylation (p-CREB) were detected by Western blot.ResultsThe results demonstrated that FTS could prevent Aβ1-42 to impair survival and neurite growth of newborn neurons in the hippocampal dentate gyrus (DG) in Aβ1-42-mice. Furthermore, behavioral indexes and morphological findings showed that FTS improved the learning and spatial memory abilities of Aβ1-42-mice. In addition, FTS could inhibit the levels of hippocampal p-ERK and p-CREB activated by Aβ, which is the underlying molecular mechanism.ConclusionIn conclusion, these findings suggest that FTS as a RAS inhibitor could be a potential therapeutic agent for the treatment of AD.

Hesperetin Confers Neuroprotection by Regulating Nrf2/TLR4/NF-κB Signaling in an Aβ Mouse Model.

Hesperetin is a bioactive flavonoid in the body, produced from hesperidin. No comprehensive studies have shown its protective effects in neurodegenerative disorders. Here, we hypothesized that hesperetin may protect the mice brain against Aβ-induced neurodegeneration. Twenty-four hours after intracerebroventricular injection of Aβ1-42, the treated group was injected hesperetin. For in vitro experiments, HT22 and BV-2 cells were used. Immunoblot, immunofluorescence, and behavioral analyses were used to evaluate the different parameters. Our results indicated that hesperetin significantly attenuated oxidative stress, as assessed by the expression of Nrf2/HO-1 and LPO and ROS assays, in the hippocampus, cortex, and in vitro HT22 cells. Similarly, activated glial cells were regulated by hesperetin, as assessed by the expression of GFAP and Iba-1. Moreover, the expression of TLR4, p-NF-κB, and downstream targets was analyzed; the results showed that hesperetin reinstated the expression of these markers. The effects of hesperetin were further confirmed by using specific TLR4 and p-NF-κB inhibitors in BV-2 cells. Next, we evaluated Aβ pathology in the cortex, hippocampus, and HT22 cells, showing that hesperetin significantly reduced the Aβ pathology. Furthermore, the antiapoptotic effects of hesperetin were assessed, which showed strong antiapoptotic effects. Overall, the neuroprotective effect of hesperetin was found to be a multipotent effect, involving the inhibition of oxidative stress, neuroinflammation, apoptotic cell death, and cognitive consolidation. Given antioxidant, anti-inflammatory, and antiapoptotic potentials against Aβ-induced neurodegeneration and memory impairment, hesperetin may be a promising therapeutic agent for Alzheimer's disease-like neurological disorders.

A15342 Interaction between Ischemic Brain Damage and Amyloid-β Infusion in Cognitive Impairment ∼Possible Amelioration of Cognitive Function by AT2 Receptor Activation∼

Objectives: We examined the possible enhancement of cognitive decline after ischemic brain damage with amyloid-β (Aβ) injection, focusing on the roles of angiotensin II type 2 (AT2) receptor in vascular smooth muscle cells (VSMC). Methods: Adult male wild-type mice (WT) or the mice with VSMC-specific AT2 receptor overexpression (smAT2) were used. Mice were subjected to intracerebroventricular (ICV) injection of Aβ1–40. Ischemic brain injury was induced by bilateral common carotid artery occlusion (BCCAO) after Aβ injection. Cognitive function was evaluated by the Morris water maze test. Results: ICV injection of Aβ in WT showed impaired cognitive function, whereas BCCAO did not decline significantly cognitive function. In contrast, BCCAO following Aβ injection exhibited more marked cognitive impairment compared to Aβ injection alone in concert with the increases in NADPH oxidase activity, expressions of NADPH oxidase subunit p22phox, p40phox and inflammatory cytokine MCP-1, IL1-β in the hippocampus. BCCAO significantly enhanced the expression of Aβ clearance factor, RAGE (receptor for advanced glycation end product). Aβ injection did not increase the neuron pyknosis in the hippocampus, whereas the number of neuron pyknosis was increased significantly with BCCAO. On the other hand, smAT2 did not show cognitive impairment, the changes of the expression for NADPH oxidase subunits, inflammatory cytokines and neuron pyknosis induced by BCCAO with/without Aβ injection in WT. Conclusion: Ischemic brain damage could enhance Aβ-induced cognitive impairment with possible involvements of enhanced oxidative stress, inflammation, neuron degeneration, and breakdown of RAGE-mediated Aβ clearance. AT2 receptor activation in VSMC might play preventive roles in this cognitive decline.

Abstract P238: Cerebral Ischemia With Amyloid-Beta Infusion Deteriorates Cognitive Decline ~Possible Amelioration of Cognitive Function by AT 2 Receptor Activation~

Objectives: Amyloid-β (Aβ) deposition in brain and cerebral vessels accelerates the pathogenesis of Alzheimer’s disease and vascular cognitive impairment. We examined possibilities that cerebral ischemia worsens Aβ infusion-mediated cognitive decline, and that angiotensin II type 2 (AT 2 ) receptor stimulation in vascular smooth muscle cells (VSMC) could ameliorate this cognitive impairment induced by cerebral ischemia and Aβ. Methods: Adult male wild-type mice (WT) and the mice with VSMC-specific AT 2 receptor overexpression (smAT 2 ) were used. Mice were subjected to intracerebroventricular (ICV) injection of Aβ1-40. Cerebral ischemia was induced by 15 minutes of bilateral common carotid artery occlusion (BCCAO) 24 hours after Aβ injection. Cognitive function was evaluated by Morris water maze test 3 weeks after Aβ injection. Results: ICV injection of Aβ in WT showed impaired cognitive function (arriving time to platform at day 5: control, 26.53±4.46 sec; Aβ, 65.35±7.44 sec), whereas BCCAO did not decline significantly cognitive function. In contrast, BCCAO following Aβ injection exhibited more marked cognitive impairment (84.27±8.00 sec) compared to Aβ injection alone in concert with the increases in superoxide anion production, NADPH oxidase activity, expressions of NADPH oxidase subunit p 22 phox , p 40 phox and inflammatory cytokines such as MCP-1, IL1-β in the hippocampus. BCCAO following Aβ injection significantly enhanced the expression of Aβ clearance factor, RAGE (receptor for advanced glycation end product). Aβ injection did not increase the neuron pyknosis in the hippocampus, whereas the number of neuron pyknosis was increased significantly with BCCAO (control, 6.33±0.88/field; Aβ with BCCAO, 46.33±4.10/field). On the other hand, smAT 2 did not show cognitive impairment, the increases in oxidative stress, inflammation markers and RAGE expression, pyknosis, which were induced by Aβ injection with/without BCCAO in WT. Conclusion: Cerebral ischemia exaggerated Aβ-induced cognitive decline with possible involvements of enhanced oxidative stress, inflammation, neuronal degeneration, and breakdown of RAGE-mediated Aβ clearance. AT 2 receptor activation in VSMC could play preventive roles in this cognitive decline.

Exercise Improves Recognition Memory and Acetylcholinesterase Activity in the Beta Amyloid-Induced Rat Model of Alzheimer’s Disease

Objective: A correlation between physical exercise and cognitive improvement has been found in Alzheimer’s disease (AD). This study aimed to investigate the effects of aerobic and resistance exercise on the recognition memory and acetylcholinesterase (AChE) activity in beta amyloid (Aβ) model of AD in rat. Materials and Methods: Fifty male 8-week-old Wistar rats (250–280 g) were divided into 5 groups (n = 10 each) of control, sham surgery, Aβ-received sedentary, Aβ-received with aerobic exercise and Aβ-received with resistance exercise. AD was induced by intracerebroventricular injection of Aβ_25–35 peptide. The sham surgery group received normal saline using the same route and condition. Two groups of Aβ-received animals were trained by treadmill for aerobic exercise and by ladder for strength exercise for 8 weeks (4 days/week). Novel object recognition (NOR) task was used to assess recognitional memory in groups. AChE activity in the brain tissue was assessed using the Spectrophotometry method. Results: There was no significant difference in memory index and AChE activity between the sham surgery and control groups (p > 0.05). Also, impairment of NOR indices was seen in the Aβ-injected sedentary rats (p < 0.05). However, both aerobic and strength training improved the exploration index in this test (p < 0.05). Further, AChE activity increased in the Aβ-injected sedentary group but declined in the aerobic and resistance exercise groups (p < 0.01). Conclusion: Aerobic and resistance exercise could improve recognition memory and decrease AChE activity in Aβ-induced AD in rats. The decrease in AChE activity may be one of the mechanisms by which exercise improves cognition and memory in AD.