Aβ Rats Research Articles

Effects of sesamin on Aβ1-42-induced oxidative stress and LTP impairment in a rat model of Alzheimer's disease.

The present study examined the protective effect of sesamin (Ses) on β-amyloid (Aβ)-induced long-term potentiation (LTP) impairment at the PP-DG synapses in male rats. Wistar rats were randomly assigned to seven groups: control, sham, Aβ; ICV Aβ1-42 microinjection, Ses, Aβ + Ses; first, ICV Aβ injections and then receiving Ses, Ses + Aβ: four weeks of pretreatment with Ses and then Aβ injection, and Ses + Aβ + Ses: pre (four weeks) and post (four weeks) treatment with Ses. Ses-treated groups received 30mg/kg of Ses once a day by oral gavage for four weeks. After the treatment period, the animals were positioned in a stereotaxic device for surgery and field potential recording. The population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were evaluated in the DG region. Serum oxidative stress biomarkers (total oxidant status (TOS) and total antioxidant capacity (TAC)) were measured. Aβ impaired LTP induction at the PP-DG synapses evidenced by a decrease in EPSP slope and PS amplitude of LTP. In Aβ rats, Ses increased EPSP slope and PS amplitude of LTP in the DG granular cells. Also, an increase in TOS and a reduction in TAC caused by Aβ were significantly corrected by Ses. Ses could prevent Aβ-induced LTP impairment at the PP-DG synapses in male rats, which can be due to its preventive effects on oxidative stress.

The Effects of Ninjinyoeito on Impaired Spatial Memory and Prefrontal Cortical Synaptic Plasticity through α-Amino-3-hydroxy-5-4-isoxazole Propionic Acid Receptor Subunit in a Rat Model with Cerebral Ischemia and β-Amyloid Injection.

Ninjinyoeito (NYT), a traditional Japanese medicine, is effective for improving physical strength and treating fatigue and anorexia. Recently, a clinical report revealed that NYT ameliorates cognitive dysfunction in Alzheimer's disease (AD) patients, although the mechanisms remain unclear. AD is a neurodegenerative disorder accompanied by a progressive deficit in memory. Current therapeutic agents are largely ineffective in treating cognitive dysfunction in AD patients. In this study, we investigated the effects of NYT on spatial memory impairment in a rat model of dementia. Rats were prepared with transient cerebral ischemia and intraventricular injection of β-amyloid1-42 for 7 days (CI + Aβ). NYT was orally administered for 7 days after cerebral ischemia. We evaluated spatial memory using the Morris water maze and investigated the expression of α-amino-3-hydroxy-5-4-isoxazole propionic acid receptor subunits, the phosphorylation level of glutamate receptor A (GluA)1 at serine sites S831 and S845, and the Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the hippocampus and prefrontal cortex of CI + Aβ rats. In the CI + Aβ rats, NYT treatment shortened the extended time to reach the platform. However, NYT did not restore the decrease in the hippocampal GluA1, GluA2, or CaMKII expression but increased prefrontal cortical phosphorylation levels of S845-GluA1 and CaMKII. Therefore, NYT may alleviate spatial memory impairment by promoting glutamatergic transmission involved in the phosphorylation of S845-GluA1 and CaMKII in the prefrontal cortex of CI + Aβ rats. Our results suggest that NYT is a valuable treatment for AD patients.

The effect of minocycline on beta-amyloid-induced memory and learning deficit in male rats: A behavioral, biochemical, and histological study

ObjectivesMinocycline hydrochloride is a semi-synthetic, second-generation tetracycline with neuroprotective, neurorestorative, anti-amyloidogenic, anti-inflammatory, antioxidant, and anti-apoptotic properties. The present study was designed to investigate the potential protective effects of minocycline against beta-amyloid (Aβ)-induced Alzheimer’s disease (AD), recognition memory decline, and the possible involved anti-apoptotic mechanisms. MethodsThe rats were treated with minocycline (50 and 100 mg/kg/day; P.O.) after AD induction for 30 days. Behavioral functions were assessed by employing standard behavioral tests, including novel object recognition (NOR) and passive avoidance learning (PAL) tasks. Then, total antioxidant capacity (TAC) and total oxidant status (TOS) were measured in blood serum using ELISA kits. Apoptosis and the number of Aβ plaques were examined by the TUNEL and Congo red staining, respectively. ResultsTreatment of Aβ rats with minocycline improved memory deficit in the PAL task and a decline in recognition memory in the NOR test. Minocycline at 50 and 100 mg/kg significantly reduced the TOS levels and increased the TAC levels (P < 0.0001). Also, minocycline at 50 and 100 mg/kg reduced the apoptotic index in the hippocampus of Aβ rats. After Congo red staining, the minocycline group showed improved cell morphology and markedly fewer Aβ plaques. ConclusionsMinocycline reduced memory and learning deficit in behavioral experiments after Aβ injection, which may be due to its anti-inflammatory and anti-apoptotic effects.

Combined Effect of Co-administration of Stromal Cell-Derived Factor-1 and Granulocyte-Colony Stimulating Factor on Rat Model of Alzheimer's Disease.

IntroductionAlzheimer’s disease (AD) is a neurodegenerative disease that is characterized by amyloid plaque deposits, neuronal cell loss, and memory impairment. Granulocyte-colony stimulating factor (G-CSF) is a growth factor associated with AD improvement. Stromal cell-derived factor-1 (SDF-1) mediates therapeutic effects of G-CSF. This study investigated the effect of combination treatment of G-CSF and SDF-1 on amyloid plaque deposits, apoptosis, and behavior of AD rats.MethodsIntracerebroventricular amyloid-beta [Aβ(1-42)] peptide was used to induce AD in Aβ rats. There were six groups including naive control, sham-operated, Aβ, Aβ + G-CSF, Aβ + SDF-1, and Aβ + G-CSF + SDF-1. SDF-1 intra-cerebroventricular (ICV), G-CSF Subcutaneous (SC), or a combination of them were administered to Aβ rats weekly for 2 months. The cognition and memory were assessed using the novel object recognition, passive avoidance, and Morris water maze tests. Next, rat brains were removed and the amyloid plaque and apoptosis were detected in the brain and hippocampus using immunohistochemistry and TUNEL assay, respectively.ResultsThe amyloid-beta and apoptotic cell levels dropped in groups receiving SDF-1 and G-CSF combination compared to the Aβ group. Also, number of microglial cells increased significantly in the combination group compared to other treatment groups. Moreover, learning and memory were significantly improved in the combination group compared to the Aβ groups (P < 0.05).ConclusionSDF-1 and G-CSF combination therapy can offer a promising strategy for AD.

Neuroprotective Effects of Poria cocos (Agaricomycetes) Essential Oil on Aβ1-40-Induced Learning and Memory Deficit in Rats.

Alzheimer's disease (AD) is a neurodegenerative disease that has become a leading cause of death in recent years. The present study aimed to explore the possible prophylactic effects of Poria cocos essential oil (PCEO) against memory deficits in Aβ rats. Adult male Wistar rats were given Aβ1-42 via ICV injection. The effect of 30 d administration of PCEO by oral gavage was investigated. Novel object recognition (NOR) test, Morris water maze (MWM) test, and passive avoidance memory retention (PAM) task were performed. Aβ decreased the cognitive memory in NOR, spatial memory in MWM, and passive avoidance memory in PAM tests. In contrast, PCEO improved learning and memory in the treated group. The PCEO treatment halts the activity of AChE in the hippocampus and cortex of the AD rats. The central neuronal degeneration in Aβ-injected rats was not only ascertained by the histopathological changes but also confirmed indirectly by the concomitant increase in GFAP immunostaining. The beneficial effects in AD of increasing cellular GPx, GR, CAT, Na+ K+ ATPase and GST through the administration of PCEO may not only result in protection against neurodegeneration but also result in improvement in cognitive function. PCEO may be recommended as a prophylactic and/or adjunct medication for neurodegenerative diseases.

Neuroprotective effects of the Chrysophyllum perpulchrum extract against an Alzheimer-like rat model of β amyloid1-40 intrahippocampal injection.

ObjectiveAlzheimer’s disease (AD) is a threatening disease for African populations in the upcoming years because of the increase in their expectancy of life. Here, we investigated whether natural products from Chrysophyllum perpulchrum as catechin and two dimeric procyanidins (catechin + hexose) could prevent progression of oxidative stress and cognitive changes using an AD-like rat model induced by Aβ1-40 injection into the hippocampal CA1 subfield.MethodologyAdult male Wistar rats were either microinjected with 1% ammonia as a vehicle (10 µL) or aggregated Aβ1-40 at 10 µg bilateral hippocampus. On the 14th day of post-surgery, some Aβ rats were treated with melatonin (10 mg/kg i.p.) or with the Chrysophyllum perpulchrum extract (300 mg/kg p.o.), and some sham-operated rats received the extract alone. Cognitive abilities were tested with Y-maze, object recognition test and Morris Water Maze. Oxidative stress markers as well as the level of activated microglial cells were assayed in the brain.ResultsAβ rats exhibited significant deficits of recognition memory and spatial learning. This was associated with an increase of microglia Iba 1 immunoreactivity as well as nitric oxide (NO), malondialdehyde and superoxide dismutase levels but not to the thiol content in the hippocampus, prefrontal cortex and septum of AD-like rats. The Chrysophyllum perpulchrum extract treatment mitigated Aβ-induced cognitive impairments and reversed microglia overactivation and subsequent generation of oxidative stress markers. Interestingly, the neuroprotective actions of the Chrysophyllum perpulchrum extract seem to be comparable to the control drug melatonin used albeit with some more beneficial effects.ConclusionThese findings are preliminary and should be strengthened by more pharmacological studies of bioactive compounds of Chrysophyllum perpulchrum before being proposed as a promising drug against AD.

Concurrent exercise does not prevent recognition memory deficits induced by beta-amyloid in rats

Alzheimer's disease affects thousands of people worldwide. Alternatives aiming to prevent the disease or reduce its symptoms include different physical exercise configurations. Here we investigate the potential of concurrent exercise to prevent recognition memory deficits in an Alzheimer's disease-like model induced by the hippocampal beta-amyloid (Aβ) injection in Wistar rats. We demonstrate that the concurrent exercise, which included running and strength exercises performed in the same exercise session, is ineffective in preventing recognition memory deficits in the Aβ rats. Besides, higher levels of reactive oxygen species were found in the concurrent exercise group's hippocampus. The running exercise administrated alone prevented recognition memory impairments.

Cognitive Disorders and Oxidative Stress Status Attenuated by Chrysophyllum Perpulchrum Extract in Alzheimer- like Rat Model of Intracerebroventricular Aβ1-40 injection

Chrysophyllum perpulchrum is an endemic medicinal plant used in ivorian tranditional pharmacopeiaeas antipyretic to heal malaria fever. Since three flavonoid compounds have been isolated, catechin and two procyanid in dimers, we are proposed to testthe neuroprotective effectiveness effects using a rat model of Alzheimer Disease (AD). Adult Wistar rats were used as model.Sham-operated rats as controlwere injected by intracerebroventricular route (i.c.v) with1% ammonia(Group1), Aβ rats were microinjected with 10µg/side (i.c.v route, (Group 2)).From 14th day post-surgery required for neuro inflammation and oxidative stress induction,some Aβ-injected rats were daily treated with the extract (300 mg/kg bw, oral route, (Group 3)) for 21 days,sham-operated rats were treated only with plant extract (300 mg/kg bw, oral route, (Group 4)). Rats were then submitted to memory tests with Y maze, object recognition test and Morris water maze. Some oxidative stress markershave been assessed.AD-like rats exhibited significant recognition memory as well as learning and spatial memory deficits.The treatment of AD like-rats with methanolic extract of Chrysophyllum perpulchrum alleviated cognitive disorders by improving the memory recognition index and spatial learning strategy to find the hidden platform. Furthermore,Chrysophyllum perpulchrum extract prevented significantly Aβ-induced lipid proxidation through a decrease of malondialdehyde (MDA) level in the hippocampus and the prefrontal cortex, and also helped to increase the non protein-thiol (NP-SH) antioxidant level.These findings suggest the neuroprotective actions of Chrysophyllum perpulchrum extract on AD-like rats. However,further pharmacological studies are needed to test ability of isolated compounds from Chrysophyllum perpulchrum to counteract full Aβ physiopathology mechanisms before promising to be a drug candidate for AD treatment.

Exposure to footshock stress downregulates antioxidant genes and increases neuronal apoptosis in an Aβ(1–42) rat model of Alzheimer's disease

Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that develops from exposure to trauma, mostly when normal psychological mechanisms fail. Studies have shown that people who have PTSD are susceptible to developing dementia, mostly Alzheimer's disease (AD), suggesting common underlying risk factors in the comorbidity. However, data elucidating links between these conditions is scarce. Here we show that footshock stress exacerbates AD-like pathology. To induce a trauma-like condition, the rats were exposed to multiple intense footshocks followed by a single reminder. This was followed by bilateral intrahippocampal lesions with amyloid-beta (Aβ) (1–42), to model AD-like pathology. We found that footshocks increased anxiety behavior and impaired fear memory extinction in Aβ(1–42) lesioned rats. We also found a reduced expression of nuclear factor erythroid 2-related factor 2 (Nrf2), NAD (P) H: quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and an increased expression of Kelch-like ECH-associated protein 1 (Keap1) in the amygdala and hippocampus. Furthermore, oxidative stress level was sustained, which was associated with increased apoptosis in the amygdala and hippocampus.Our finding suggests that AD-like pathology can induce oxidative changes in the amygdala and hippocampus, which can be exaggerated by footshock stress.

The Molecular Mechanism of Scutellaria baicalensis Georgi Stems and Leaves Flavonoids in Promoting Neurogenesis and Improving Memory Impairment by the PI3K-AKT-CREB Signaling Pathway in Rats.

The aim of this study was to investigate the effect and molecular mechanism of Scutellaria baicalensis Georgi stems and leaves flavonoids (SSF) in promoting neurogenesis and improving memory impairment induced by the PI3K-AKT-CREB signaling pathway. Alzheimer's disease (AD) was induced in the male Wistar rats by intracerebroventricular injection of amyloid beta peptide 25-35 (Aβ25-35) in combination with aluminum trichloride (AlCl3) and recombinant human transforming growth factor-β1(RHTGF-β1) (composited Aβ). The Morris water maze was used to screen the successful establishment of the memory impairment model of rats. The screened successful model rats were randomly divided into a model group and three groups of three different doses of the drug (SSF). Rats in the drug group were treated with 35, 70, and 140 mg/kg of SSF for 43 days. The Eight-arm maze was used to measure the spatial learning and memory abilities of the rat, including working memory errors (WME) and reference memory errors (RME). Immunohistochemistry was used to detect the expression of BrdU, an indicator of neuronal proliferation, in the hippocampal gyrus of rats. The mRNA and protein expressions of TRKB, PI3K, AKT, P-AKT, and IGF2 in the PI3K-AKT-CREB signaling pathway in the hippocampus and cerebral cortex of the rats were determined by quantitative real-time PCR (qPCR) and Western blotting methods. Compared to the sham group, the spatial memory ability of rats with composited Aβ was decreased, the number of WME and RME (P < 0.01) was increased, the expression of BrdU protein (P < 0.01) in the hippocampal gyrus was reduced, the mRNA and protein expression levels of TRKB, AKT, and IGF2 (P < 0.01, P < 0.05) in the hippocampus and cerebral cortex were lowered, and the mRNA expression level of PI3K (P < 0.01) in the cerebral cortex and the protein expression level of PI3K (P < 0.01) in the hippocampus were augmented. However, compared to the model group, the three-doses of SSF improved memory disorder induced by composited Aβ, reduced the number of WME and RME, increased the expression of BrdU protein in the hippocampal gyrus, and differently regulated the mRNA and protein expressions in composited Aβ rats. SSF improved memory impairment and neurogenesis disorder induced by composited Aβ in rats by activating the PI3K-AKT-CREB signaling pathway and up-regulating the mRNA and protein expressions of TRKB, PI3K, AKT, CREB, and IGF2.

Protective effects of intracerebroventricular adiponectin against olfactory impairments in an amyloid β1–42 rat model

BackgroundAlzheimer’s disease (AD) is characterized by cognitive impairment that eventually develops into dementia. Amyloid-beta (Aβ) accumulation is a widely described hallmark in AD, and has been reported to cause olfactory dysfunction, a condition considered an early marker of the disease associated with injuries in the olfactory bulb (OB), the hippocampus (HIPP) and other odor-related cortexes. Adiponectin (APN) is an adipokine with neuroprotective effects. Studies have demonstrated that APN administration decreases Aβ neurotoxicity and Tau hyperphosphorylation in the HIPP, reducing cognitive impairment. However, there are no studies regarding the neuroprotective effects of APN in the olfactory dysfunction observed in the Aβ rat model. The aim of the present study is to determine whether the intracerebroventricular (i.c.v) administration of APN prevents the early olfactory dysfunction in an i.c.v Amyloid-beta1–42 (Aβ1–42) rat model. Hence, we evaluated olfactory function by using a battery of olfactory tests aimed to assess olfactory memory, discrimination and detection in the Aβ rat model treated with APN. In addition, we determined the number of cells expressing the neuronal nuclei (NeuN), as well as the number of microglial cells by using the ionized calcium-binding adapter molecule 1 (Iba-1) marker in the OB and, CA1, CA3, hilus and dentate gyrus (DG) in the HIPP. Finally, we determined Arginase-1 expression in both nuclei through Western blot.ResultsWe observed that the i.c.v injection of Aβ decreased olfactory function, which was prevented by the i.c.v administration of APN. In accordance with the olfactory impairment observed in i.c.v Aβ-treated rats, we observed a decrease in NeuN expressing cells in the glomerular layer of the OB, which was also prevented with the i.c.v APN. Furthermore, we observed an increase of Iba-1 cells in CA1, and DG in the HIPP of the Aβ rats, which was prevented by the APN treatment.ConclusionThe present study describes the olfactory impairment of Aβ treated rats and evidences the protective role that APN plays in the brain, by preventing the olfactory impairment induced by Aβ1–42. These results may lead to APN-based pharmacological therapies aimed to ameliorate AD neurotoxic effects.

Effects of vanillic acid on Aβ1-40-induced oxidative stress and learning and memory deficit in male rats

Alzheimer's disease (AD) is a neurodegenerative disease, in which the accumulation of β-amyloid (Aβ) peptide in the extracellular space causes a progressive reduction in cognitive performance. Aβ stimulates active oxygen species generation leading to oxidative stress and neural cell death. Vanillic Acid (VA) is the oxidant form of vanillin widely found in vanilla beans. VA has many properties, such as suppressing apoptosis and eliminating the harmful effects of oxidative stress in animal models. The VA effects on impaired learning and memory in Aβ rats were assessed. Forty adults male Wistar rats were assigned to the following five groups in random: the control, sham (received saline (vehicle) via intracerebroventricular (ICV) injection), Aβ (received Aβ1–40 via ICV injection), VA (50 mg/kg by oral gavage once a day through four weeks), and Aβ + VA (50 mg/kg) groups. Open field test, novel object recognition (NOR) test, Morris water maze (MWM) test, and passive avoidance learning (PAL) task were performed, and finally, we determined the malondialdehyde (MDA), total antioxidant capacity (TAC) and total oxidant status (TOS) levels. Aβ decreased the cognitive memory in NOR, spatial memory in MWM, and passive avoidance memory in PAL tests. In contrast, VA improved learning and memory in the treated group. Aβ significantly increased MDA and TOS and decreased TAC levels, whereas VA treatment significantly reversed TAC, TOS and MDA levels. In conclusion, VA decreased the Aβ effects on learning and memory by suppressing oxidative stress and can be regarded as a neuroprotective substance in AD.

Evaluation of neuroprotective potential of methanolic extract of Hemidesmus indicus extract in Aβ (1-42) induced rats

Excessive cerebral deposition of amyloid-beta (Aβ) peptides with 40-42 amino acids are the major neuropathologic feature of Alzheimer's Disease (AD), accompanied by a progressive and functional decline in cognition. With the failing attempts in the development of new pharmacological intervention and due to suboptimal results from the existing therapies available for the treatment of AD, there is a constant hunt for a new therapeutic alternative to address this severe neurodegenerative disease. The present study aimed to investigate the neuroprotective effect of Hemidesmus indicus extract in Aβ (1-42) infused model of AD. Sporadic model of AD was achieved by intracerebroventricular (i.c.v) injection of Aβ (1-42) peptide in Wistar rats, followed by treatment with methanolic extract of H. indicus (MEHI) at 100 and 200 mg/kg for 28 days. Locomotor activity, Radial arm Maze task and Passive avoidance test were used for the assessment of neurobehavioral deficits. After completion of 28 days treatment protocol, animals were euthanized and brains were collected for neurochemical analysis. Reversal of cognitive impairment was observed by MEHI on Aβ (1-42) rats, as evidenced by improved spatial memory learning. Furthermore, MEHI attenuated Aβ (1-42) induced oxidative stress and inhibited acetylcholine esterase (AChE) activity. Collectively, these findings exhibited neuroprotective activity of MEHI by ameliorating Aβ (1-42) mediated neuronal damage, thereby can stand as a potential disease-modifying therapeutic for curbing AD pathology.

Long-term exposure to constant light induces dementia, oxidative stress and promotes aggregation of sub-pathological Aβ42 in Wistar rats

Constant exposure to light is prevalent in modern society where light noise, shift work, and jet lag is common. Constant light exposure disrupts circadian rhythm, induces stress and thus influences memory performance. We subjected adult male Wistar rats to a two-month exposure to constant light (LL), constant dark or normal light-dark cycles. Significant cognitive impairment and oxidative stress were observed in LL rats without a significant elevation in soluble Aβ1–42 levels. Next, we examined whether long-term exposure to constant light may accelerate dementia in a sub-pathological Aβ model of rats. Normal control rats received ACSF, AD rats received 440 pmol, and sub-pathological Aβ rats (Aβ(s)) received 220 pmol of human Aβ42 peptide in a single unilateral ICV administration. Sub-pathological Aβ rats exposed to constant light (LL + Aβ(s)) show significant memory deficits and oxidative damage, although not significantly different from LL rats. Additionally, constant light promoted aggregation of exogenous Aβ42 in LL + Aβ(s) rats shown by the presence of congophilic plaques. Furthermore, chronic fluoxetine treatment (5 mg/kg/day) rescued rats from the behavioral deficits, oxidative damage and amyloid aggregation. Whereas, rifampicin treatment (20 mg/kg/day) did not reverse the behavioral deficits or oxidative stress but rescued rats from amyloid plaque formation. It was concluded that constant light for two months induces behavioral deficits, oxidative stress, and accelerates aggregation of sub-pathological concentrations of human-Aβ42 peptides in Wistar rats, which is reversed by daily fluoxetine administration.

The protective and therapeutic effects of vinpocetine, a PDE1 inhibitor, on oxidative stress and learning and memory impairment induced by an intracerebroventricular (ICV) injection of amyloid beta (aβ) peptide

Alzheimer’s disease (AD) is a neurodegenerative disease leading to cognitive and memory impairment. This study aimed at investigating the therapeutic and preserving effects of vinpocetine on amyloid beta (Aβ)-induced rat model of AD. Sixty male adult Wistar rats were randomly divided into 6 groups (n = 10 per group) as follows: 1; control, 2; sham, 3; Aβ, 4; pre-treatment (vinpocetine + Aβ): oral gavage administration of vinpocetine at 4 mg/kg for 30 days followed by intracerebroventricular (ICV) injection of Aβ, 5; treatment (Aβ + vinpocetine): Aβ ICV injection followed by vinpocetine administration for 30 days, 6; pre-treatment + treatment (vinpocetine + Aβ + vinpocetine): vinpocetine administration for 30 days before and 30 days after AD induction. Following treatments, the animals’ learning and memory were investigated using passive avoidance learning (PAL) task, Morris water maze (MWM), and novel object recognition (NOR) tests. The results demonstrated that Aβ significantly enhanced escape latency and the distance traveled in the MWM, decreased step-through latency, and increased time spent in the dark compartment in PAL. Vinpocetine ameliorated the Aβ-infused memory deficits in both MWM and PAL tests. Administration of vinpocetine in the Aβ rats increased the discrimination index of the NOR test. It also significantly diminished the nitric oxide and malondialdehyde levels and restored the reduced glutathione (GSH) levels. Vinpocetine can improve memory and learning impairment following Aβ infusion due to its different properties, including antioxidant effects, which indicates that vinpocetine administration can lead to the amelioration of cognitive dysfunction in AD.

Effects of Cyperus rotundus Extract on Spatial Memory Impairment and Neuronal Differentiation in Rat Model of Alzheimer's Disease.

Background:Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in the older population and characterized by progressive memory and cognitive impairment. Cyperus rotundus, a traditional medicinal herb, has analgesic, sedative, and anti-inflammatory effects and also used to increase memory in Islamic traditional medicine. This study was designed to consider the effects of C. rotundus extract on memory impairment and neurogenesis in the Beta-Amyloid rats' model.Materials and Methods:Forty-two male Wistar rats were randomly divided into six groups (n = 7) for the evaluation of baseline training performance in the Morris water maze test. Then, amyloid-beta (Aβ1-42) was injected in animal hippocampal CA1 bilaterally in four groups. The first probe trial was performed 21 days after Aβ injection. Then, 250, 500, and 750 mg/kg of C. rotundus extract were administered to three Aβ-injected groups for 1 month; after that, the second probe trial was performed, and rats were sacrificed after 28 days of the second probe trial. The neurogenesis was detected in the hippocampus, by immunohistochemical staining.Results:This study showed that spatial memory increased in the behavioral test in AD treated group with C. rotundus extract, compared with the AD group (P = 0.02). Immunohistochemical staining revealed that neuronal differentiation has been occurred in the hippocampus in the AD-treated group with C. rotundus extract compared with the AD group (P = 0.01).Conclusions:This study showed that C. rotundus extract, repaired spatial memory impairment in the Aβ rats, through increased neurogenesis in the hippocampus, which could be related to the flavonoid components in the extract.

The spatial cerebral damage caused by larger infarct and β-amyloid toxicity is driven by the anatomical/functional connectivity.

Large cerebral infarctions are major predictors of death and severe disability from stroke. Conversely, data concerning these types of infarctions and the affected adjacent brain circuits are scarce. It remains to be determined if the co-morbid concurrence of large infarct and β-amyloid (Aβ) toxicity can precipitate the early development of dementia. Here, we described a dose-dependent effect of a unilateral striatal injection of vasoconstrictive endothelin-1 (ET-1) along with Aβ toxicity on CNS pathogenesis; driven by the anatomical and functional networks within a brain circuit. After 21 days of treatment, a high dose (60 pmol) of ET-1 (E60) alone caused the greatest increase in neuroinflammation, mainly in the ipsilateral striatum and distant regions with synaptic links to the striatal lesion such as white matter (subcortical white matter, corpus callosum, internal capsule, anterior commissure), gray matter (globus pallidus, thalamus), and cortices (cingulate, motor, somatosensory, entorhinal). The combined E60 + Aβ treatment also extended perturbation in the contralateral hemisphere of these rats, such as increased deposition of amyloid precursor protein fragments associated with the appearance of degenerating cells and the leakage of laminin from the basement membrane across a compromised blood-brain barrier. However, the cerebral damage induced by the 6 pmol ET-1 (E6), Aβ and E6 + Aβ rats was not detrimental enough to injure the complete network. The appreciation of the causal interactions among distinct anatomical units in the brain after ischemia and Aβ toxicity will help in the design of effective and alternative therapeutics that may disassociate the synergistic or additive association between the infarcts and Aβ toxicity.

Effect of Riluzole, a Glutamate Release Inhibitor, on Synaptic Plasticity in the Intrahippocampal Aβ Rat Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is associated with cognitive deficits of varying degrees and with impairment of the synaptic transmission-related tasks. Pathologically, AD is highlighted with accumulation of extracellular β-amyloid plaques and of neurofibrillary tangles. Glutamate-mediated neurotoxicity plays a pivotal role in the pathogenesis of AD. Deficits of long-term potentiation (LTP) and neuronal synaptic plasticity as an essential mechanism of the learning and memory disorders in AD has been ascribed to over-activation of glutamate receptors. We examined the effect of riluzole, a glutamate release inhibitor, on LTP impairment in the dentate gyrus (DG) in a rat model of AD provided by bilateral intrahippocampal amyloid β (Aβ 25-35) injections; riluzole was administered at a dose of 10 mg/kg. The LTP in perforant path-DG synapses was evaluated using measurements of the field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude. We found that Aβ (25–34) significantly decreased the fEPSP slope and PS amplitude, as compared to those in the sham group; riluzole pretreatment in the Aβ-microinjected group significantly increased these parameters. Taken together, it is concluded that riluzole could noticeably improve synaptic plasticity and enhan ce LTP in the rat model of AD.

A\u03b2-induced vulnerability propagates via the brain\u2019s default mode network

The link between brain amyloid-β (Aβ), metabolism, and dementia symptoms remains a pressing question in Alzheimer’s disease. Here, using positron emission tomography ([18F]florbetapir tracer for Aβ and [18F]FDG tracer for glucose metabolism) with a novel analytical framework, we found that Aβ aggregation within the brain’s default mode network leads to regional hypometabolism in distant but functionally connected brain regions. Moreover, we found that an interaction between this hypometabolism with overlapping Aβ aggregation is associated with subsequent cognitive decline. These results were also observed in transgenic Aβ rats that do not form neurofibrillary tangles, which support these findings as an independent mechanism of cognitive deterioration. These results suggest a model in which distant Aβ induces regional metabolic vulnerability, whereas the interaction between local Aβ with a vulnerable environment drives the clinical progression of dementia.

Spatial Dynamics of Vascular and Biochemical Injury in Rat Hippocampus Following Striatal Injury and Aβ Toxicity.

The hippocampus, a brain region vital for memory and learning, is sensitive to the damage caused by ischemic/hypoxic stroke and is one of the main regions affected by Alzheimer's disease. The pathological changes that might occur in the hippocampus and its connections, because of cerebral injury in a distant brain region, such as the striatum, have not been examined. Therefore, in the present study, we evaluated the combined effects of endothelin-1-induced ischemia (ET1) in the striatum and β-amyloid (Aβ) toxicity on hippocampal pathogenesis, dictated by the anatomical and functional intra- and inter-regional hippocampal connections to the striatum. The hippocampal pathogenesis induced by Aβ or ET1 alone was not severe enough to significantly affect the entire circuit of the hippocampal network. However, the combination of the two pathological states (ET1 + Aβ) led to an exacerbated increase in neuroinflammation, deposition of the amyloid precursor protein (APP) fragments with the associated appearance of degenerating cells, and blood-brain-barrier disruption. This was observed mainly in the hippocampal formation (CA2 and CA3 regions), the dentate gyrus as well as distinct regions with synaptic links to the hippocampus such as entorhinal cortex, thalamus, and basal forebrain. In addition, ET1 + Aβ-treated rats also demonstrated protracted loss of AQP4 depolarization, dissolution of β-dystroglycan, and basement membrane laminin with associated IgG and dysferlin leakage. Spatial dynamics of hippocampal injury in ET1 + Aβ rats may provide a valuable model to study new targets for clinical therapeutic applications, specifically when areas remotely connected to hippocampus are damaged.