Quantifying Uncertainty and Sensitivity in an Alzheimer's Disease Model: A Mathematical Approach.

Animal Models of Alzheimer's Disease

Alzheimer's disease is one of the prevalent neurodegenerative diseases and is characterized by amyloid beta aggregate (Aβ) accumulation. This study reports an Aβ 1–42 induced 3D Alzheimer's disease modeling utilizing differentiated SH‐SY5Y spheroids, which is carried out by Magnetic levitation approach, and the neuroprotective effect of Curcumin is further investigated on this model. For this purpose, SH‐SY5Y spheroids are differentiated using Retinoic acid‐Brain‐derived neurotrophic factor sequentially during 3D cell culture. Differentiated spheroids maintained high viability and exhibited significant neuronal characteristics, as evidenced by increasing β‐III tubulin and NeuN expressions. 3D Alzheimer's disease model formation and neurotoxicity of Aβ 1–42 aggregates are investigated on un‐/differentiated spheroids, resulting in 65% and 51% cell viability, respectively. Characterization of the 3D Alzheimer's disease model is done by immunostaining of Choline acetyltransferase to investigate cholinergic neuron activity loss, showing a 2.2 decrease in fluorescence intensity. Further, Curcumin treatment on the 3D Alzheimer's disease model resulted in augmenting cell viability, confirming neuroprotective effect of Curcumin on Aβ 1–42 induced Alzheimer's disease model. This study highlighted the magnetic levitation‐based fabrication of Aβ 1‐42‐induced 3D Alzheimer's disease model successfully, offering a promising experimental platform for other neurodegenerative disease research and potential clinical applications.

Objective To investigate the effect of Fructus arctii extract on Alzheimer disease (AD) model of mice and its mechanism. Methods Fifty healthy male Kunming mice were randomly divided into 5 groups, respectively, the negative control group, AD model group, Oxiracetam Capsules (400 mg/kg) and Fructus arctii extract (FAE 800 mg/kg, 400 mg/kg). The AD model was intraperitoneally injected with D-galactose 100 mg/kg and aluminum trichloride 10 mg/kg by intragastric administration every day. Since the 15th day of AD model developed, the mice in experimental groups were intragastric administrated with the corresponding dosage each day for 45 days. Behavioral testing in exposed and control mice were developed using step-down assays and water maze test, and the chemical parameters SOD, T-AOC, MDA, [Ca2+], NO and NOS of brain tissue were measured. Differences among groups were compared by SPSS statistics software using ANOVA. Results Compared with model group, the latency period in step-down assays was statistically lengthened and the whole swimming time in water maze test was reduced in the FAE groups, and the rate of errors was decreased in step-down tests (F=11.07, P=0.004. F=8.13, P=0.011, F=6.25, P=0.02). The chemical parameter showed that the levels of MDA, NO, NOS and [Ca2+] in brain tissue were significantly decreased in the FAE group (F=5.12, P=0.04 F=4.49, P=0.05, F=4.55, P=0.05, F=4.62, P=0.05) and the activity of the SOD and T-AOC (F=6.49, P=0.02. F=4.76, P=0.05) increased greatly. Conclusions The FAE can protect the deficit of learning and memory of the AD model mice. The mechanisms of effects may be related to the improvement of enzymes, reduce the formation of free radical; resulting in prevention of peroxide generation and reduction of NO-related neurological damage. Key words: Fructus arctii; Alzheimer disease; Learning and memory; Model

Effects of exercise on brain-derived neurotrophic factor in Alzheimer's disease models: A systematic review and meta-analysis

The effect of Ginkgo biloba (GB) on mitochondria-dependent TRPV1 ion channels in neuroblastoma cells was investigated by creating an Alzheimer's disease (AD) model. Okadaic acid was applied on SH-SY5Y cells to create an AD model. After cellular differentiation, the study was organized with the seven main groups, examining the effect of GB on calcium depended TRPV1 channels in neuroblastoma cells AD, has been established in vitro. The higher Ca2+ concentration was detected in the GB+AD, AD and AD+GB groups when compared with the control (p<0.001). The Ca2+ level was lower in GB+AD and AD+GB groups than in the AD group (p<0.001). Also, cytosolic Ca2+ concentration was lower in the GB+AD than in the AD+GB group (p<0.05), the apoptosis and intracellular reactive oxygen species (ROS) values were higher in the GB+AD, AD and AD+GB groups than in the control (p<0.001). The apoptosis and intracellular ROS values were higher in AD group than in the GB+AD and AD+GB group (p<0.001) and the apoptosis level was higher in AD+GB group than GB+AD group (p<0.001) and the mitochondrial depolarization, caspase 3 and caspase 9 levels were higher in the GB+AD, AD and AD+GB groups when compared to the control group (p<0.001). Also, the values were lower in the GB+AD group, AD group and AD+GB groups when compared with the GB+AD+capsazepine group, AD+capsazepine group and AD+GB+capsazepine respectively (p<0.001). These results show us that GB has a protective effect besides its therapeutic effect in Alzheimer's disease via TRPV1 channel.

The study aimed to examine the behavior ability and morphological changes in neuron in the hippocampal CA3 area of Alzheimer's disease (AD) model rats induced by β-amyloid protein (Aβ1–42) and observe the potentiality of the neuroprotective effect of basic fibroblast growth factor (bFGF) on the AD model rats. A total of 70 Wistar rats were randomly divided into the normal control group, the AD model group and the bFGF treatment group. The AD model rats were established by microinjection of Aβ1–42 solution into right hippocampal CA1 area. The bFGF was injected into the abdominal cavity of rats in the bFGF treatment group, and identical volume physiological saline was given for the other two groups. The colorimetric method was used to detect the choline acetyltransferase (ChAT) and acetylcholinesterase (AchE) activity after the behavior capability was determined. Real time-PCR (RT-PCR) was used to evaluate the expression of VEGF mRNA of the rat hippocampal CA3 area. Caspase-3 immunopositive cells in the hippocampal CA3 area were observed under a light microscopy and quantitative analysis were performed by cell morphometric technique. The ultra-microstructure of the neurons was also observed by a transmission electron microscopy (TEM). The results indicated that compared with the AD model group, the learning and memory abilities of the bFGF treatment group were obviously improved and the ChAT activity significantly increased (p &lt; 0.05), whereas the AChE activity, expression of VEGF mRNA and quantity of Caspase-3 immunopositive cells notably decreased (p &lt; 0.05). Under TEM, the neurons in the hippocampal CA3 area of the normal control group had moderate electron density, rule nucleus, integrity perinuclear membrane, evenly distributed chromoplasm and abundant cell organelle, however the neurons of the AD model group showed severely damaged, exhibiting cell body pyknosis, irregular nuclear membranes concentrated, intracytoplasm content concentrated, decreased or unclear organelles. The neuronic pathological lesion of the bFGF treatment group had lessened than that of the AD model group; some of them had distinct neuronal structure and abundant cell organelle. BFGF could efficiently improve the behavior ability and decrease the pathological lesion of hippocampus of the AD model rats, which might promote the neuroprotective effect in the AD.

Objective To investigate the effects of tenuigenin (TEN) on expression of brain-derived neurotrophic factor (BDNF), and its receptor tyrosine protein kinase B (TrkB) in the hippocampal CA1 region of Alzheimer's disease (AD) model rats. Methods Sixty male Wistar rats were divided randomly into 4 groups: the control group, the model group, 12.50 mg/ml TEN group and 37.50 mg/ml TEN group. AD model rats were made by injecting ibotenic acid into Meynert basal nuclei of aging rats induced by D-galactose. The expressions of BDNF and its receptor TrkB in the hippocampal CA1 region were measured by immunohistochemistry method. Results The positive expressions of BDNF and TrkB were pale brown and mainly in neuronal cell membrane of the hippocampal CA1 region measured by immunohistochemistry method. The average absorbance values of BDNF and its receptor TrkB in the control group were 0.47 ± 0.02 and 0.46 ± 0.05, while in the model group were 0.30 ± 0.02 and 0.21 ± 0.07 which were significantly lower than that of the control group (P = 0.000, for all). The average absorbance values of BDNF and its receptor TrkB in 12.50 mg/ml TEN group were 0.35 ± 0.05 and 0.32 ± 0.07, which were significantly higher than that of the model group ( P = 0.000, for all) and 37.50 mg/ml TEN group were 0.43 ± 0.05 and 0.37 ± 0.03, which were significantly higher than that of the model group ( P = 0.000, for all). The average absorbance values of BDNF and its receptor TrkB in 37.50 mg/ml TEN group increased significantly than that in 12.50 mg/ml TEN group ( P = 0.000). Conclusions TEN can dose-dependently increase BDNF and its receptor TrkB expression in the hippocampal CA1 region of Alzheimer's disease model rats, which may partly explain the beneficial effects of TEN on cognitive function. doi: 10.3969/j.issn.1672-6731.2014.05.011

BackgroundAlzheimer's disease is associated with dementia and occurs due to the misfolding and extracellular accumulation of amyloid‐beta (Aβ) protein in the brain. Aβ25‐35 peptide is a toxic form of Aβ commonly used in in vitro models. Although no definitive cure exists, several FDA‐approved drugs help patients maintain mental function. Bioactive peptides are specific protein fragments and are distinguished by their ability to promote positive effects on different neurodegenerative diseases. Bioactive peptides derived from hazelnuts (Corylus avellana L.) hold promise for neuroprotective effects against Alzheimer's disease.MethodAlzheimer's disease model was established using PC‐12 cell line treated with Aβ25‐35. Toxic doses for the disease model were determined using resazurin‐based cell viability assays. Subsequently, bioactive peptide derived from hazelnuts were applied to the Alzheimer's disease model, and the neuroprotective effect doses were identified through cell viability assays. Colony forming unit assay was performed to analyze the growth inhibition on Alzheimer's disease model. Cell cycle and Annexin V/PI assay was evaluated using flow cytometry. 2′,7′‐dichlorofluorescin diacetate (DCF‐DA) reagent was used to detect intracellular ROS production by fluorescent microscopy.ResultOC1 bioactive peptide from hazelnut ameliorated the cell viability of in vitro Alzheimer's model. OC1 peptide was further evaluated for their neuroprotective effects at the molecular level. Cell cycle analysis revealed that Alzheimer's model group (Aβ25‐35 treated) showed G2/M phase arrest in cell cycle assay when compared to control. Conversely OC1 peptide treatment improved the G2/M arrest caused by Aβ25‐35. Annexin V/PI results demonstrate that Aβ25‐35 treated group induced late apoptosis, while OC1 peptide treatment reversed this effect. OC1 peptide exerted neuroprotective effect by reducing intracellular ROS formation compared to Aβ25‐35 treated alone.ConclusionOur findings indicate that the newly synthesized bioactive peptide OC1 is promising as potential neuroprotective agents for neurodegenerative diseases and may offer encouraging results for the prevention of Alzheimer's disease.This study was supported by Türkiye Sağlık Enstitüleri Başkanlığı, grant number: 22740 TÜSEB. Attendance at this conference was supported by an AAIC 2025 Conference Fellowship.

Objective To investigate the effect of inosine on the neuronal apoptosis and the expressions of Bcl-2 and Bax in Alzheimer's disease(AD)model in rats induced with beta-amyloid proteinl-40(Aβ_(1-40))injection,and to explore some mechanism of inosine in improving the capability of learning and memory.Methods Thirty adult healthy male wistar rats were randomly divided into control group(n=10),model group(n=10)and treated group(n=10).The AD models were estabhshed by injecting Aβ_(1-40) stereotactically into the left lateral ventricle,and treated by injecting inosine(100mg·kg~(-1))intraperitoneally.The learning and memory capacity of rats was evaluated with Y-electric maze.HE staining was used to observe the structure.The neuronal apoptosis was investigated by TUNEL assay.The expressions of Bcl-2 and Bax were determined with immunohistochemistry assay.Results Compared with control group(59.13±7.52,7.94±2.21),the model group rats showed disorder cognitive ability(79.84±6.46,4.83±3.14)and abnormal cell structure(t=5.67,2.25 P＜0.05).The number of neuronal apoptosis and the expressions of Bcl-2 and Bax protein increased significantly than those in control group (P＜0.05).Compared with model group(81.22±3.92,4.61±1.60),inosine improved strikingly cognitive ability(68.54±8.86,7.14±1.13)and cell structure(t=3.46,4.64,P＜0.05).The expressions of Bcl-2(33.52±5.68)increased and Bax(25.11±2.45)while the number of neuronal apoptosis(23.40± 7.07)decreased markablely than those(20.24±1.32,41.82±3.71,35.51±2.30)in model group(t=6.04,9.94,4.30 P＜0.05).Conclusion Inosine might decrease the neuronal apoptotic rate by enhancing Bcl-2 and inhibiting Bax expressions,which improve learning and memory capacity of AD rats. Key words: Inosine; Alzheimer's disease; Beta-amyloid protein; Apoptosis

Treadmill exercise improve recognition memory by TREM2 pathway to inhibit hippocampal microglial activation and neuroinflammation in Alzheimer's disease model

Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

Memory loss in Alzheimer's disease: are the alterations in the UPR network involved in the cognitive impairment?

HDAC3 inhibition has been shown to improve memory and reduce amyloid-β (Aβ) in Alzheimer's disease (AD) models, but the underlying mechanisms are unclear. We investigated the molecular effects of HDAC3 inhibition on AD pathology, using invitro and exvivo models of AD, based on our finding that HDAC3 expression is increased in AD brains. For this purpose, N2a mouse neuroblastoma cells as well as organotypic brain cultures (OBCSs) of 5XFAD and wild-type mice were incubated with various concentrations of the HDAC3 selective inhibitor RGFP966 (0.1-10 μM) for 24 h. Treatment with RGFP966 or HDAC3 knockdown in N2a cells was associated with an increase on amyloid precursor protein (APP) and mRNA expressions, without alterations in Aβ42 secretion. Invitro chromatin immunoprecipitation analysis revealed enriched HDAC3 binding at APP promoter regions. The increase in APP expression was also detected in OBCSs from 5XFAD mice incubated with 1 μM RGFP966, without changes in Aβ. In addition, HDAC3 inhibition resulted in a reduction of activated Iba-1-positive microglia and astrocytes in 5XFAD slices, which was not observed in OBCSs from wild-type mice. mRNA sequencing analysis revealed that HDAC3 inhibition modulated neuronal regenerative pathways related to neurogenesis, differentiation, axonogenesis, and dendritic spine density in OBCSs. Our findings highlight the complexity and diversity of the effects of HDAC3 inhibition on AD models and suggest that HDAC3 may have multiple roles in the regulation of APP expression and processing, as well as in the modulation of neuroinflammatory and neuroprotective genes.

Microglia rely on SYK signalling to mount neuroprotective responses in models of Alzheimer's disease and multiple sclerosis.

Objective To explore the methods of labeling exogenous microglia with superparamagnetie iron oxide(SPIO)particles,and to monitor the labeled cells after transplantation into the normal rat and Alzheimer's disease(AD)model rat with MR scanning.Methods Microglia was labeled with SPIO particles by using transfection agent,hemagglutinating virus of Japan envelope(HVJ-E).Then the microglias which were labeled with SPIO were injected into the internal carotid artery of normal rat (n=5)and AD model rat(n=5).Three days after transplantation,follow-up serial T2*-weighted gradient-echo MR imaging was performed at 7.0T MRI system.MR images were correlated with histological findings.Results In the brain of normal rat,the labeled microglias were demonstrated as several dotty signalintensity decrease on T2*-weighted MR images.The dotty spots were sporadic around the brain.Histological analysis showed that most prussian blue staining-positive cells were well correlated with the area where a signal intensity decrease was observed in MRI.MR could detect the signal intensity change caused by a few labeled cells.In the brain of AD model rat,MR scan showed a well-defined hypointensity area in the region of Aβ42 iniection.Signal intensity decrease was not obvious in the region of saline injection.The number of iron-positive cells(454±47)/mm2 at sites of Aβ42 injection was much higher than that(83±13)/mm2 of saline injection(P＜0.05). Conclusion MR can be used as a non-invasive means of detecting transplanted labeled microglia in vivo,with the potential for future clinical application in cell therapy of AD. Key words: Microglia; Alzheimer disease; Magnetic resonance imaging; Rats