جستجوی مقالات مرتبط با کلیدواژه "amyloid-beta" در نشریات گروه "پزشکی"

The main pathological features of Alzheimer’s disease (AD) include the cytotoxic extracellular accumulation of the amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles. The Aβ plaques are responsible for cholinergic dysfunction and dementia in AD patients. Immunoglobulin G (IgG) and Aβ form an immune complex that activates neuroglia, clearing Aβ from the brain. Various Aβ-based therapeutic strategies have been proposed to reduce Aβ production, inhibit Aβ aggregation, and increase Aβ clearance. New medicines, such as aducanumab and donanemab, which are human IgG1 monoclonal antibodies, reduce cognitive impairment in patients with AD by decreasing the amount of Aβ plaques. Despite the considerable advantages of these agents, some disadvantages have also been reported, including Aβ-related imaging abnormalities, anaphylaxis, high cost, and contradictory results. Moreover, donanemab has delivered contradictory outcomes in improving recognition and performance in AD. However, although not fully proven yet, fewer side effects are reported for donanemab compared to aducanumab. Therefore, this review aims to explore the research background, compare the mechanism of action, and understand the advantages and disadvantages of aducanumab and donanemab. As a result, these medicines with maximum effectiveness and safety, yet fewer side effects, could be developed for future treatment and references.

Alzheimer’s disease (AD) is a neurodegenerative disease that results in the gradual breakdown of brain tissue, causing the deterioration of intellectual function and ability. Crocin is a saffron carotenoid compound proven to have excellent neuroprotective and anti-inflammation properties, although it has some limitations such as low stability and bioavailability. Therefore, in the current research, we tried to improve these limitations by using nanotechnology and chitosan as the carrier. Our study examined the therapeutic effects of crocin nano-chitosan-coated compound and compared it with intact crocin in lower dosages than other studies in AD rat models. 

Encapsulating crocin into chitosan nanoparticles was done through a modified technique to improve its limitations. The AD rat model was induced by bilaterally injecting beta-amyloid (Aβ) peptide into the frontal lobe using a stereotaxic device. To evaluate memory, we conducted the Barnes maze test, and to evaluate anxiety, we used the elevated plus maze test. Also, histological tests were conducted to evaluate neuronal damage in each group. 

Crocin nano-chitosan-coated administration significantly improved specific memory indicators compared to the Aβ and other treated groups. A significant decrease in anxiety indicators was detected compared to the Aβ and other treated groups. Finally, the results of hippocampus staining indicated a meaningful difference between the Aβ group and other treated groups, compared to the crocin nano-chitosan-coated group. 

Treatment with low dosages of crocin in the nano-coated form exhibited great efficacy in reducing AD’s adverse effects compared to the same dosage of intact crocin.

Oxidative stress plays an important role in Alzheimer’s disease (AD) pathogenesis. Moringa oleifera leaf (MOL) extract has been shown to have antioxidant activities. Here, we studied the antioxidative and anti-apoptotic effects of water-soluble MOL extract in an amyloid beta (Aβ)-induced oxidative stress model of AD.

Experimental approach: 

The effect of amyloid beta (Aβ)1-42 and MOL extract on differentiated SH-SY5Y cell viability was assessed by MTT assay. Cells were treated with Aβ1-42, MOL extract, or MOL extract followed by Aβ1-42. The mitochondrial membrane potential (ΔΨm) and the reactive oxygen species (ROS) were evaluated by flow cytometry and dihydroethidium (DHE) assay, respectively. Western blotting was used to assess the expression of mitochondrial proteins TIMM23 and NDUFS3, apoptosis-related proteins Bax, Bcl-2, and cleaved caspase-3 along with fluorescence analysis of caspase-3/7, and Akt phosphorylation.

MOL extract pretreatment at 25, 50, and 100 μg/mL prevented ΔΨm reduction. At 100-μg/mL, MOL extract decreased TIMM23 and NDUFS3 proteins and DHE signals in Aβ1-42-treated cells. MOL extract pretreatment (25, 50, and 100 μg/mL) also alleviated the apoptosis indicators, including Bax, caspase-3/7 intensity, and cleaved caspase-3, and increased Bcl-2 levels in Aβ1-42-treated cells, consistent with a reduction in the number of apoptotic cells. The protective effects of MOL extract were possibly mediated through Akt activation, evidenced by increased Akt phosphorylation.

Conclusion and implications: 

The neuroprotective effect of MOL extract could be mediated via the activation of Akt, leading to the suppression of oxidative stress and apoptosis in an Aβ1-42 model of AD.

Alzheimer's disease (AD) is a common neurodegenerative disease and the fifth leading cause of death among the elderly. The development of drugs for AD treatment is based on inhibiting cholinesterase (ChE) activity and inhibiting amyloid-beta peptide and tau protein aggregations. Many in vitro findings have demonstrated that thiazole- and thiazolidine-based compounds have a good inhibitory effect on ChE and other elements involved in the AD pathogenicity cascade.

Experimental approach: 

In the present review, we collected available documents to verify whether these synthetic compounds can be a step forward in developing new medications for AD. A systematic literature search was performed in major electronic databases in April 2021. Twenty-eight relevant in vitro and in vivo studies were found and used for data extraction.

Findings demonstrated that thiazole- and thiazolidine-based compounds could ameliorate AD's pathologic condition by affecting various targets, including inhibition of ChE activity, amyloid-beta, and tau aggregation in addition to cyclin-dependent kinase 5/p25, beta-secretase-1, cyclooxygenase, and glycogen synthase kinase-3β.

Conclusion and implications: 

Due to multitarget effects at micromolar concentration, this review demonstrated that these synthetic compounds could be considered promising candidates for developing anti-Alzheimer drugs.

Dysregulation of brain cholesterol homeostasis causes the accumulation of extracellular protein deposits called amyloid plaques in the hippocampus which eventually leads to neuronal death, memory and learning deficits. The aim of the present study was to investigate the effect of beta amyloid on miRNAs regulating HMGCR and ABCA1 as cholesterol synthesis and homeostasis genes. Primary astrocytes were isolated from C57BL/6J mice, and were treated with 0.5 μM amyloid beta (Aβ). Expression levels of genes and miRNAs were measured by real-time PCR. In comparison to control, Aβ treatment resulted in a significant decrease in miR-96-5p expression as a positive and negative regulator of HMGCR and ABCA1, respectively. There was no significant increase in miR-27a-3p expression as a negative regulator of HMGCR. miR-106b-5p and miR-143-3p expressions were also dramatically decreased as ABCA1 negative regulators. Amyloid beta can alter the expression of major genes in the cholesterol homeostasis pathway via their regulatory miRNAs.

Amyloid-beta (Aβ) production is a normal physiological process, and an imbalance in Aβ production/excretion rate is the basis of the plaque load increase in AD. LRP1 is involved in both central clearance of Aβ from the CNS and transport of Aβ toward peripheral organs. In this study, the effect of silymarin combination compared to rosuvastatin and placebo on neuro-metabolites and serum levels of LRP1 and Aβ1-42 proteins and oxidative stress enzymes and lipid and cognitive tests of Iranian AD patients.

In this double-blind placebo-controlled study, thirty-six mild AD patients were divided into groups (n=12) of silymarin 140mg, placebo, and rosuvastatin 10mg. Medications were administered 3 times a day for 6 months. Clinical tests, lipid profile (TG, HDL, TC, and LDL), Aβ1-42, and LRP1 markers were measured at the beginning and end of the intervention. Magnetic resonance spectroscopy (MRS) was used to measure metabolites. Using SPSS software a one-way ANOVA test was used to compare the means of the quantitative variables and Pearson and Spearman's correlations to measure the correlation. GraphPad Prism software was used for drawing graphs. P < 0.05 was considered a significant.

The levels of LRP1 and Aβ1-42 in the silymarin group were significantly increased compared to the other groups (P < 0.05). NAA/mI in the silymarin group had a significant increase compared to both placebo and rosuvastatin groups (P < 0.05). Right and left hippocampal mI/Cr directly correlated with TG (r = 0.603, P = 0.003 and r = 0.595, P = 0.004, respectively). NAA/Cr of the right and left hippocampus was inversely related to TG (r = -0.511, P = 0.0033, and r = -0.532, P = 0.0021, respectively). NAA/Cr and NAA/mI of bilateral hippocampi directly correlated with HDL (P < 0.05). An inverse correlation was observed between the Aβ1-42 and mI/Cr of the right and left hippocampus (r = -0.661, P = 0.000 and r = -0.638, P = 0.000, respectively).

Donepezil and silymarin improved lipid profile associated with increased NAA/Cr, and decreased mI/Cr, in AD patients. Biomarker NAA/mI can be clinically significant in examining AD pathology. Measurement of the lipid factors and neurometabolites can be a suitable method for monitoring this disease.

 Alzheimer's disease (AD), the most common neurodegenerative disease in the world, appears in two forms, early and late. Pathologically, an amyloid beta peptide is the hallmark of this disease which is followed by synaptic dysfunction, brain atrophy, and accumulation of neuronal tangles. The purpose of this study is to review the researchers on astrocytes' role in the progress of AD.

 A comprehensive search was conducted in databases articles focusing on key terms "Inflammatory reactions", "Alzheimer's disease", "Inflammatory factors" and "Astrocytes" and Boolean operators. Articles before 2001 were removed.

 Finally, After analyzing the selected articles, 20 articles were extracted and included in this review.

 Astrocytes are a group of glial cells in the central nervous system. The inflammatory activity of astrocytes plays a role in the development and progression of Alzheimer's disease. They strengthen the function of synapses by secreting neurotrophic factors. They also clear amyloid beta peptides from nerve tissue. Amyloid beta peptides bind to specific receptors on these cells and change the activity of these cells from anti-inflammatory to inflammatory type.It seems that astrocytes play a pivotal role in the development and progression of AD, particularly at the late stage of the disease. Finding a rational strategy to suppress inflammatory A1 phenotype might be a promising tool to slow down the progress of AD.

Estradiol has been shown to facilitate synaptic long-term potentiation (LTP) mainly through translocation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor from intracellular pool to the post synaptic membrane. On the other hand, oligomeric amyloid beta (oAβ) decreases number of AMPA receptors in the synapses. It is well known that trafficking of AMPA receptors is governed by an atypical and autonomously active isoform of PKC called protein kinase M zeta (PKMζ). In spite of these evidence, the effect of estradiol on PKMζ expression is not yet studied. We aim to examine the possible protective effect of estradiol on PKMζ and AMPA receptor subunits against oAβ in hippocampal primary cell culture.

Primary cell culture was prepared from postnatal (P0 to P3) rat pups. They were decapitated and the brains were removed. Hippocampi were isolated and collected in cold phosphate buffer saline. Then, they were trypsinized at 37°C for 15min. The cells were treated with 1µM OAβ or vehicle for 24h and then with 100nM estradiol for another 24h. Using the western blot analysis, the expression level of AMPAR subunit glutamate receptor 1 (GluA1), GluA2 and PKMζ were determined.

OAβ decreased the level of GluA1, GluA2 and PKMζ. Estradiol did not change the molecule levels in healthy cells; however, it preserved their expression levels in OAβ treated cells.

These findings suggest that estradiol may restore expression level of synapse related molecules in an Alzheimer’ disease cell model, in part, through acting on PKMζ signaling pathway.

Increasing evidence indicates that oxidative stress is an important factor in the pathogenesis and progression of Alzheimer’s disease (AD). Betaine is trimethylglycine with antioxidant and neuroprotective properties. The present study aimed to evaluate the possible beneficial effects of betaine on oxidative stress and memory deficits induced by intrahippocampal injection of amyloid beta (Aß) in an AD model. 

Experimental approach:

 Forty adult male Wistar rats were divided into 5 equal groups: the control and Aß groups which received oral gavage of saline (1 mL daily) for 14 days. The other 3 groups (betaine + Aß) received betaine (5, 10, and 15 mg/kg, orally) for 14 consecutive days. On the 15th day, all of the groups were injected bilaterallyintrahippocampal of Aß (5 μg/μL), except controls that were injected with normal saline as a vehicle. Seven days after the Aß injection, memory was assessed in a passive avoidance test. Changes in catalase activities and glutathione peroxidase, glutathione, and malondialdehyde concentrations were investigated to determine the antioxidant activity in the rat hippocampus.

Data showed that betaine pretreatment of Aß-injected rats improved memory in avoidance tasks. In addition, betaine pretreatment attenuated oxidative stress.

Conclusion and implications:

 The current findings showed that oral administration of betaine could prevent Aß-induced impairment of memory possibly through suppression of oxidative stress in the hippocampus area of rats.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia in the old age population, making it a worldwide concern. Unfortunately, few drugs have been presented for treatment of mild and moderate AD. To meet this need, more effective anti-AD agents are emerging. Accumulating evidence supports the beneficial roles of natural-based products in brain function, neurotransmission, neurogenesis, synaptogenesis, and the prevention of amyloid fibrillation and neuronal injury. Several in vitro, preclinical, and clinical studies suggest that saffron (its bioactive compounds) is a potential nutraceutical with antioxidant, radical scavenging, anti-inflammatory, hypolipidemic, hypotensive, neuroendocrine, and neuroprotective effects. It has also been proposed that saffron may delay the onset of AD, prevent its progression or help to attenuate the symptoms of the disease. Therefore, we performed a comprehensive search on this plant and its derivatives for AD treatment. Saffron and its active constituents interfere with AD by improving learning behavior, spatial memory, and cognitive function; protecting against neuronal loss; inhibiting beta-amyloid aggregation and neurotoxicity; preventing senile plaques and neurofibrillary tangle (NFT) formation; suppressing the acetylcholinesterase (AChE) activity; and reducing neuroinflammation. Given conclusive scientific findings, saffron and its derivatives might counter neurodegenerative diseases through multiple pathways. Further clinical trials are expected to confirm the neuroprotective properties of this herb and also to translate such findings to improve patients’ outcomes.

One of the main causes of Alzheimer's disease is an increase in amyloid-beta (Aβ) peptides, which are produced by the activity of the enzyme gamma-secretase (γ-secretase). Although exercise and the use of royal jelly have protective effects on neurons, there is limited information about their interactive effects, so the present study was performed to investigate the effect of eight weeks of positive slope training (PST) and negative slope Training (NST), along with the use of royal jelly (RJ) on the hippocampal expression of Aβ and γ-secretase in Alzheimer's rats treated with trimethyltin (TMT). 

In this experimental study, 42 male rats were injected intraperitoneally with 8 mg/kg TMT and were randomly assigned to seven groups of 6 subjects, including: (1) sham (royal jelly solvent), (2) PST, (3) NST, (4) PST+RJ, (6) NST+RJ and (7) RJ were divided. To assess the effects of Alzheimer's induction on variables, six rats were included in the healthy control group. Rats performed endurance training for eight-weeks, five days per week, and 60 minutes per session and the royal jelly groups received 100 mg/kg royal jelly peritoneally each day for eight weeks. 

PST, NST, and RJ decreased the expression of Aβ and γ-secretase (P <0.001). Also, PST+RJ and NST+RJ decreased the expression of Aβ and γ-secretase in the hippocampal tissue of rats with Alzheimer's disease (P <0.001). 

It seems that PST, NST, and RJ can reduce the progression of Alzheimer's disease markers, and PST+RJ and NST+RJ synergistically reduce the progression of Alzheimer's disease in animal models.

Dementia is a disease in which memory, thinking, and cognitive skills are impaired, with Alzheimer’s being the most common type of dementia. Brassica nigra is useful for eliminating memory loss in traditional Persian medicine. This study aims to examine the effect of B. nigra fixed oil (BNO) on the changes in memory caused by β-amyloid.

This research was conducted on 42 Wistar rats divided into 7 groups (n=6) including 1) control (received vehicle), 2) the group receiving BNO (925 and 462.5 mg/kg), 4) sham group 5) Alzheimer group (receiving 50 ng/µl/side β-amyloid in CA1 area of hippocampus) and 2 groups receiving β-amyloid along with two different doses of BNO. The daily gavage of BNO was done 2 to 21 days post amyloid injection. The spatial memory was evaluated in Morris water maze from day 21 to 26.

The results of this study revealed that the gavage of BNO (925 mg/kg) to rats receiving β-amyloid, as compared to those receiving β-amyloid alone, significantly decreased the traveled distance and the required time for finding hidden platform on the training days and increased the time of presence in the target quadrant on the test days. The analysis of BNO with GC-MS revealed that Erucic acid (24.79%) and 11-Eicosenoic acid (17.23%) had the highest content in the BNO.

Regarding the presence of unsaturated fatty acids, it is likely that the consumption of BNO can play an important role in the prevention of memory degradation which warrants further clinical studies.

Synaptic plasticity is inappropriately affected by neurodegenerative diseases, including Alzheimer Disease (AD). In this study, we examined the effect of intrahippocampal amyloid-beta (Aβ1-40) on dentate gyrus Long-term Potentiation (LTP) and presynaptic short-term plasticity in a rat model of AD. 

The experimental groups in this research included the control with no treatment, sham-operated receiving the vehicle (normal saline), and Aβ-lesioned groups. For modeling AD, aggregated Aβ1-40 (10 μg/2 μl on each side) was injected into the hippocampal CA1. Three weeks later, Population Spike (PS) amplitude and slope ratios were determined at different Inter-pulse Intervals (IPI) of 10, 20, 30, and 50 ms as a valid indicator of the short-term presynaptic facilitation and/or depression. In addition, PS amplitude and slope were taken as an index of long-term synaptic plasticity after application of High-frequency Stimulation (HFS) to induce LTP in the medial perforant-dentate gyrus pathway. 

No significant differences were noted amongst the experimental groups regarding fEPSP slope and paired-pulse indices as indicators of short-term plasticity. In contrast, fEPSP slope and PS amplitude significantly decreased following the application of HFS in Aβ-injected group. In addition, there was no significant difference between the control and sham-operated groups regarding the mentioned parameters. 

Findings of this study clearly demonstrated that microinjection of Aβ1-40 into the CA1 could impair LTP in dentate gyrus but could not modify short-term plasticity.

Alzheimer disease (AD) is a neurodegenerative disorder characterized by the progressive loss of memory and other cognitive functions. Protein kinase Cε (PKCε) is an isoform that most effectively suppresses amyloid beta (Aβ) production and synaptic loss.

In this study, spatial learning and memory for treated rats were evaluated by the Morris water maze test. The activity (total PKC), mRNA expression, and protein level of PKCε in the platelet and hippocampal tissue were evaluated using immunosorbent assay, real-time qPCR, and western blotting analysis, respectively. 

The traveled distance was significantly prolonged, and escape latency significantly increased in Aβ-treated groups. PKC activity assay showed that there was a remarkable difference between the Aβ-treated and sham-operated groups on days 10 and 30 in the hippocampus and also day 30 in platelet after the injection of Aβ. A significant effect in PKC activity was observed between days 0 and 10, days 0 and 30, as well as days 5 and 30. Aβ significantly downregulated the PKCε mRNA expression in the hippocampus of rats on day 30; however, no significant difference was observed in platelet. Western blot analysis demonstrated that Aβ significantly reduced PKCε protein expression in the hippocampus of treated groups on day 30. 

The expression level of PKCε was downregulated following the injection of Aβ in the hippocampus, but no significant difference was observed between the AD and sham groups in platelet that may be due to the low concentration of PKCε or duration of Aβ exposure in the rat brain.

Alzheimer’s disease (AD) and obesity are recognized as main health problems in aging, and both cause changes in blood cells and blood factors.

The purpose of this study was to evaluate the effects of virgin coconut oil (VCO) on hematological and biochemical changes as well as serum oxidative status in an amyloid-β (Aβ) receiving rat that fed a high fat diet (HFD).

A total of 100 male Wistar rats were divided into 10 groups, including: healthy control, HFD, HFD + 8% VCO, HFD + 10% VCO, Aβ (Alzheimer’s model), Aβ + 8% VCO, Aβ + 10% VCO, HFD + Aβ, HFD + Aβ + 8% VCO, HFD + Aβ + 10% VCO. One week after the surgery, HFD, 8% and 10% VCO were used for eight weeks. After that, blood samples were collected. The total antioxidant capacity, total oxidant status, hematological factor, calcium (Ca), and phosphate levels were determined.

Aβ and HFD induced oxidative stress condition in the serum. They also affected the number of blood cells including red blood cells, white blood cells, lymphocyte, and platelet, and some hematological and biochemical change status such as hemoglobin, hematocrit, Ca, and phosphate (P < 0.05). VCO significantly normalized these effects of Aβ and HFD (P < 0.01).

It could be concluded that VCO improved blood cells and blood factors status, probably by scavenging free radicals and improving the antioxidant status of Alzheimer’s in rats fed on HFD.