Activity In Alzheimer's Disease Research Articles

Virtual structure-based docking and molecular dynamics of FDA-approved drugs for the identification of potential IKKB inhibitors possessing dopaminergic activity in Alzheimer’s disease

In Alzheimer's disease (AD), neuroinflammation is detrimental in causing neurodegeneration. In the central nervous system, inhibitor of nuclear factor kappa B kinase subunit beta (IKK2/IKKβ/IKKB/IKBKB) signaling is linked to neuroinflammation-mediated learning and memory deficits through canonical pathway, while dopamine agonists have been known to reverse such effects. Our in silico analysis predicted if dopaminergic agonists could have IKKB inhibitory actions, to ameliorate neuroinflammation-associated learning and memory deficits. Here, the FDA-approved Zinc 15 database was screened with IKKB (PDB ID 4KIK). Potential molecules with IKKB inhibition were identified through docking, which also possessed dopaminergic activity. Molecular mechanics—generalized Born and surface area (MMGBSA), induced fit docking (IFD) and molecular dynamic (MD) studies of 100 ns simulation time were done. Apomorphine and rotigotine showed greater non-bonding and bonding interactions with amino acids of IKKB as compared to Aripiprazole in docking studies. The IFD studies predicted improved interactions with IKKB. MMGBSA scores indicated that the complex binding free energies were favorable, and MD studies showed an acceptable root mean square deviation between protein and ligands. The protein–ligand interactions showed hydrogen bonds, water and salt bridges necessary for IKKB inhibition, as well as solvent system stability. On the protein–ligand contact map, the varying color band intensities represented the ligand’s ability to bind with amino acids. Dopamine agonists apomorphine, rotigotine, and aripiprazole were predicted to bind and inhibit IKKB in in silico system.Graphical

Identification and Prioritization of PET Neuroimaging Targets for Microglial Phenotypes Associated with Microglial Activity in Alzheimer's Disease.

Activation of microglial cells accompanies the progression of many neurodegenerative disorders, including Alzheimer's disease (AD). Development of molecular imaging tools specific to microglia can help elucidate the mechanism through which microglia contribute to the pathogenesis and progression of neurodegenerative disorders. Through analysis of published genetic, transcriptomic, and proteomic data sets, we identified 19 genes with microglia-specific expression that we then ranked based on association with the AD characteristics, change in expression, and potential druggability of the target. We believe that the process we used to identify and rank microglia-specific genes is broadly applicable to the identification and evaluation of targets in other disease areas and for applications beyond molecular imaging.

CSF immune activation in Alzheimer’s disease driven by tau‐ and not amyloid pathology

AbstractBackgroundGenetic studies suggest involvement of the immune system in Alzheimer’s disease (AD) development, and neuroinflammation has been suggested as a key driver of AD. We here employ cerebrospinal fluid (CSF) markers to study whether immune‐ and glial activation are primary features of early amyloid plaque deposition, or follow significant tau pathology as the disease progresses.MethodWe included n=267 non‐demented cases with repeated CSF samples (1‐6 years). The presence of amyloid pathology (A), tau‐tangle pathology (T) and neurodegeneration (N) using Aß42/40 ratio, p‐tau181 and total‐tau were determined at baseline and follow‐ups. We then selected participants (n=226) that remained stable A‐/T‐/N‐ (n=134), A+/T‐/N‐ (n=33) and A+/T+/N+ (n=34) over time and cases that progressed from A‐/T‐/N‐ to A+/T‐/N‐ (n=14) and A+/T‐/N‐ to A+/T or N+ (n=11). Other A/T/N categories (e.g. A‐/T or N+) were excluded. Mixed Linear Models (MLMs) were used to measure longitudinal changes in CSF sTREM2, YKL‐40, clusterin, fractalkine, MCP‐1, IFN‐γ, IL‐6, IL‐18 and IL‐10 between groups with stable A‐/T‐/N‐ group as the reference. All models included age, sex and number of APOEε4 alleles as covariates.ResultCompared to stable A‐/T‐/N‐, cases progressing from A‐/T‐/N‐ to A+/T‐/N‐ had lower sTREM2 levels (p=.022) over time, and both fractalkine (p=.053), IFN‐γ (p=.055) and clusterin levels (p=.068) showed trend levels towards lower levels. In stable A+/T‐/N‐ cases, YKL‐40 (p=.007) and fractalkine (p=.043) were lower than stable A‐/T‐/N‐ over time. A+/T+/N+ cases had markedly higher sTREM2, fractalkine and clusterin levels (all p<.001) that remained high over time. In this group the YKL‐40 levels were also higher at baseline (p<.001) and increased slightly over time (p=.032). There were no between‐group differences at neither baseline or over time in the CSF levels of MCP‐1, IL‐6, IL‐18 and IL‐10.ConclusionAmyloid pathology alone was not associated with increased immune and glial activation in our cohort, and several of the CSF immune markers were lower in both those progressing to A+/T‐/N‐ and the stable A+/T‐/N‐. An increase in activation markers was only shown in cases with tau‐pathology at baseline, or in cases that developed tau pathology during the follow‐up period, suggesting immune activation in response to tau pathology.

Cx3cr1 deficiency aggravates Aβ driven neurodegeneration and cognitive decline in a mouse model of Alzheimer's disease.

AbstractBackgroundDespite its identification as a key checkpoint regulator of microglial activation in Alzheimer’s disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau in is not well understood.MethodUsing 4 ‐ and 6‐month old 5xFAD;Cx3cr1+/+ and 5xFAD;Cx3cr1‐/‐ mice, we use immunohistochemistry, western blotting, transcriptomic analysis and quantitative real time PCR to investigate accumulation of soluble and insoluble Aβ species, plaque associated microglial activation, synaptic dysregulation and neurodegeneration with disease progression. Flow cytometry based, Aβ uptake assays are used for in‐vivo characterization of the effects of CX3CR1‐signaling on microglial phagocytosis and degradation of methoxy‐X04+ fibrillar Aβ. Lastly, we use Y‐maze testing to analyze the effects of Cx3cr1 deficiency on working memory in 5xFAD mice.ResultWe show that disease progression in 5xFAD;Cx3cr1‐/‐ mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement, along with impaired microglial Aβ phagocytosis and lysosomal acidification in‐vivo. Interestingly, Cx3cr1 deficiency resulted in heighted accumulation of neurotoxic, oligomeric Aβ, which correlated with severe neuritic dystrophy, preferential loss of post‐synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA coupled with real time PCR validation using FACS‐purified microglial cells revealed dysregulated TGFβ responses, inflammatory signaling and oxidative stress responses in 5xFAD;Cx3cr1‐/‐ mice.ConclusionIn contrast to increased Aβ uptake by Cx3cr1‐/‐ microglia during early disease, Cx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering an accumulation of neurotoxic soluble and insoluble Aβ species with disease progression. Our results indicate that Aβ‐driven microglial dysfunction in Cx3cr1‐/‐ mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory. This study underscores the importance of investigating the time‐dependent role of CX3CR1‐driven microglial responses in AD.

Relationships Between the Deposition of Amyloid-β and Tau Protein and Glymphatic System Activity in Alzheimer's Disease: Diffusion Tensor Image Study.

Amyloid-β (Aβ) and tau protein accumulation in the brain is thought to be one of the causes of Alzheimer's disease (AD). Recent study found that the glymphatic system was waste drainage system in the brain and promoting the elimination of Aβ and tau protein. We evaluated the relationships between the glymphatic system activity and the Aβ and tau protein deposition. Subjects were 21 patients with AD and 36 healthy subjects who underwent diffusion tensor imaging (DTI) scan and the positron emission tomography (PET) using with the Aβ tracer: 11C-PiB and the tau/inflammatory tracer: 18F-THK5351. We computed diffusion tensor image analysis along the perivascular space (DTI-ALPS) index as the proxy of glymphatic system activity, and estimated the relationships between the DTI-ALPS index and Aβ and tau protein/inflammatory deposition. We found significant negative correlations between DTI-ALPS index and the standard uptake value ratio (SUVR) of 11C-PiB in the bilateral temporal and left parietal cortices and left posterior cingulate gyrus in all subjects. Further, we detected significant negative correlations between DTI-ALPS index and the SUVR of 18F-THK5351 in the bilateral temporal cortices and right parietal cortex in all participants, too. Our data suggested that DTI-ALPS index was a good biomarker for the evaluation of Aβ and tau deposition and neuroinflammation, and this marker might be effective to estimate the glymphatic system activity.

Saussurea costus for sustainable and eco-friendly synthesis of palladium nanoparticles and their biological activities

Palladium nanoparticles have been evaluated as a viable candidate in the realm of biological applications due to their unique features. Saussurea costus extract was used as a stabilizing and reducing agent for the synthesis of palladium nanoparticles with average grain size of 17.6 ± 1.2 nm. The synthesized PdNPs were evaluated for their antioxidant activity, anti Alzheimer's activity, antibacterial and anticancer activities. The nanocharacterization was carried out using different spectroscopic techniques, including UV–visible spectroscopy, Transmission Electron Microscopy, Fourier Transformed Infrared spectroscopy, X-ray Diffraction analysis, X-ray Photoelectron spectroscopy, Energy Dispersive X-ray Spectroscopy, Size distribution, and Zeta potential. The characterization data explained the PdNPs mediated by S.costus extract have spherical form and are disseminated without agglomeration. FTIR and XPS supported the hypotheisis that the biomolecules of S.costus are activing as a reducing and stabilizing agents. The antioxidant activity of PdNPs was assessed using a free radical scavenging assay (DPPH) which exhibited similar results to the ABTS assay i.e. 90 μg/mL IC50 value. Moreover Alzheimer's disease can easily be inhibited by S.costus@PdNPs at 400 mg/mL, with 79.23 ± 1.11 % of inhibition rate against AChE and 76.13 ± 0.43 % towards BChE. S.costus@PdNPs showed comparatively greater antibacterial activity against all four Staphylococcus aureus, Bacillus subtilis Escherichia coli and Pseudomonas aeruginosa microorganisms. Supplementary research carried out on the anti-tumor effects of the generated PdNPs using the colon cancer (HCT-116), hepatocellular carcinoma (HepG2), and breast adenocarcinoma (MCF-7) cell lines. PdNPs showed potent anticancerous activity against all the cell lines. Thus we recommend S.costus@PdNPs as a thearapeutic agent after successful clinical trails in future.

Static and Dynamic Functional Connectivity Alterations in Alzheimer's Disease and Neuropsychiatric Diseases.

Background: To date, numerous studies have documented various alterations in resting brain activity in Alzheimer's disease (AD) and other neuropsychiatric diseases. In particular, disease-related alterations of functional connectivity (FC) in the resting state networks (RSN) have been documented. Altered FC in RSN is useful not only for interpreting the phenotype of diseases but also for diagnosing the diseases. More recently, several studies proposed the dynamics of resting-brain activity as a useful marker for detecting altered RSNs related to AD and other diseases. Objectives: In this article, we review recent studies exploring alterations of static and dynamic functional connectivity in AD and other neuropsychiatric diseases. We then discuss how to utilize and interpret dynamics of FC for studying resting brain activity in diseases. Results: In contrast to previous studies, which focused on FC calculated using an entire fMRI scan (static FC), newer studies focused on the temporal dynamics of FC within the scan (dynamic FC) to provide more sensitive measures to characterize RSNs. However, despite the increasing popularity of dynamic FC, several statistical investigations of dynamic FC cautioned that the results obtained in commonly used analyses for dynamic FC require careful interpretation. Conclusions: Although static and dynamic FC are likely to be a useful tool to detect altered RSN in patients affected by AD and other neuropsychiatric disorders, interpretation of altered dynamic FC in patients require special care. Impact statement We review recent studies of static and dynamic functional connectivity (dFC) in Alzheimer's disease and discuss interpretation of dFC.

Cell type-specific inference of differential expression in spatial transcriptomics.

A central problem in spatial transcriptomics is detecting differentially expressed (DE) genes within cell types across tissue context. Challenges to learning DE include changing cell type composition across space and measurement pixels detecting transcripts from multiple cell types. Here, we introduce a statistical method, cell type-specific inference of differential expression (C-SIDE), that identifies cell type-specific DE in spatial transcriptomics, accounting for localization of other cell types. We model gene expression as an additive mixture across cell types of log-linear cell type-specific expression functions. C-SIDE's framework applies to many contexts: DE due to pathology, anatomical regions, cell-to-cell interactions and cellular microenvironment. Furthermore, C-SIDE enables statistical inference across multiple/replicates. Simulations and validation experiments on Slide-seq, MERFISH and Visium datasets demonstrate that C-SIDE accurately identifies DE with valid uncertainty quantification. Last, we apply C-SIDE to identify plaque-dependent immune activity in Alzheimer's disease and cellular interactions between tumor and immune cells. We distribute C-SIDE within the R package https://github.com/dmcable/spacexr .

Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer's models.

The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer's disease (AD). Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also display improved cognition and reduced microglia activation compared with controls. Clinical data indicate that FMD cycles are feasible and generally safe in a small group of AD patients. These results indicate that FMD cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain.

Dual PET-fMRI reveals a link between neuroinflammation, amyloid binding and compensatory task-related brain activity in Alzheimer’s disease

The interplay among neuropathological mechanisms underlying Alzheimer’s disease (AD), as neuroinflammation and amyloid-beta (Aβ), as well their impact on neuronal function remains elusive. A major gap in knowledge is the functional impact of neuroinflammation. The posterior cingulate cortex (PCC), as the most prominent site of amyloid pathology in AD, is a pivotal region to investigate the concomitant presence of pathophysiological mechanisms such as microglia activation, indexing neuroinflammation, and changes in task related activity. Here we used a dual PET approach to simultaneously study Aβ load and neuroinflammation (TSPO uptake marker), using 11C-PiB and 11C-PK11195 radiotracers, respectively and fMRI to study task related neural activation in an AD sample (n = 19) and matched controls (n = 19). Here we show significantly increased Aβ deposition, neuroinflammation and brain activity related to a visual object working memory task in this key region. Microglia activation was associated with increased brain activity specifically in patients, independently of amyloid binding, raising the possibility that abnormal brain activity might be restored in clinical trials aimed at reducing microglia activation.

Galectin-3 is elevated in CSF and is associated with Aβ deposits and tau aggregates in brain tissue in Alzheimer’s disease

Galectin-3 (Gal-3) is a beta-galactosidase binding protein involved in microglial activation in the central nervous system (CNS). We previously demonstrated the crucial deleterious role of Gal-3 in microglial activation in Alzheimer’s disease (AD). Under AD conditions, Gal-3 is primarily expressed by microglial cells clustered around Aβ plaques in both human and mouse brain, and knocking out Gal-3 reduces AD pathology in AD-model mice. To further unravel the importance of Gal-3-associated inflammation in AD, we aimed to investigate the Gal-3 inflammatory response in the AD continuum. First, we measured Gal-3 levels in neocortical and hippocampal tissue from early-onset AD patients, including genetic and sporadic cases. We found that Gal-3 levels were significantly higher in both cortex and hippocampus in AD subjects. Immunohistochemistry revealed that Gal-3+ microglial cells were associated with amyloid plaques of a larger size and more irregular shape and with neurons containing tau-inclusions. We then analyzed the levels of Gal-3 in cerebrospinal fluid (CSF) from AD patients (n = 119) compared to control individuals (n = 36). CSF Gal-3 levels were elevated in AD patients compared to controls and more strongly correlated with tau (p-Tau181 and t-tau) and synaptic markers (GAP-43 and neurogranin) than with amyloid-β. Lastly, principal component analysis (PCA) of AD biomarkers revealed that CSF Gal-3 clustered and associated with other CSF neuroinflammatory markers, including sTREM-2, GFAP, and YKL-40. This neuroinflammatory component was more highly expressed in the CSF from amyloid-β positive (A+), CSF p-Tau181 positive (T+), and biomarker neurodegeneration positive/negative (N+/−) (A + T + N+/−) groups compared to the A + T−N− group. Overall, Gal-3 stands out as a key pathological biomarker of AD pathology that is measurable in CSF and, therefore, a potential target for disease-modifying therapies involving the neuroinflammatory response.

CX3CR1 deficiency aggravates amyloid driven neuronal pathology and cognitive decline in Alzheimer’s disease

BackgroundDespite its identification as a key checkpoint regulator of microglial activation in Alzheimer’s disease, the overarching role of CX3CR1 signaling in modulating mechanisms of Aβ driven neurodegeneration, including accumulation of hyperphosphorylated tau is not well understood.MethodologyAccumulation of soluble and insoluble Aβ species, microglial activation, synaptic dysregulation, and neurodegeneration is investigated in 4- and 6-month old 5xFAD;Cx3cr1+/+ and 5xFAD;Cx3cr1−/− mice using immunohistochemistry, western blotting, transcriptomic and quantitative real time PCR analyses of purified microglia. Flow cytometry based, in-vivo Aβ uptake assays are used for characterization of the effects of CX3CR1-signaling on microglial phagocytosis and lysosomal acidification as indicators of clearance of methoxy-X-04+ fibrillar Aβ. Lastly, we use Y-maze testing to analyze the effects of Cx3cr1 deficiency on working memory.ResultsDisease progression in 5xFAD;Cx3cr1−/− mice is characterized by increased deposition of filamentous plaques that display defective microglial plaque engagement. Microglial Aβ phagocytosis and lysosomal acidification in 5xFAD;Cx3cr1−/− mice is impaired in-vivo. Interestingly, Cx3cr1 deficiency results in heighted accumulation of neurotoxic, oligomeric Aβ, along with severe neuritic dystrophy, preferential loss of post-synaptic densities, exacerbated tau pathology, neuronal loss and cognitive impairment. Transcriptomic analyses using cortical RNA, coupled with qRT-PCR using purified microglia from 6 month-old mice indicate dysregulated TGFβ-signaling and heightened ROS metabolism in 5xFAD;Cx3cr1−/− mice. Lastly, microglia in 6 month-old 5xFAD;Cx3cr1−/− mice express a ‘degenerative’ phenotype characterized by increased levels of Ccl2, Ccl5, Il-1β, Pten and Cybb along with reduced Tnf, Il-6 and Tgfβ1 mRNA.ConclusionsCx3cr1 deficiency impairs microglial uptake and degradation of fibrillar Aβ, thereby triggering increased accumulation of neurotoxic Aβ species. Furthermore, loss of Cx3cr1 results in microglial dysfunction typified by dampened TGFβ-signaling, increased oxidative stress responses and dysregulated pro-inflammatory activation. Our results indicate that Aβ-driven microglial dysfunction in Cx3cr1−/− mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation and impairs working memory.

Effect of the ABCA1 agonist CS-6253 on amyloid-β and lipoprotein metabolism in cynomolgus monkeys

BackgroundInducing brain ATP-binding cassette 1 (ABCA1) activity in Alzheimer’s disease (AD) mouse models is associated with improvement in AD pathology. The purpose of this study was to investigate the effects of the ABCA1 agonist peptide CS-6253 on amyloid-β peptides (Aβ) and lipoproteins in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys, a species with amyloid and lipoprotein metabolism similar to humans.MethodsCS-6253 peptide was injected intravenously into cynomolgus monkeys at various doses in three different studies. Plasma and CSF samples were collected at several time points before and after treatment. Levels of cholesterol, triglyceride (TG), lipoprotein particles, apolipoproteins, and Aβ were measured using ELISA, ion-mobility analysis, and asymmetric-flow field-flow fractionation (AF4). The relationship between the change in levels of these biomarkers was analyzed using multiple linear regression models and linear mixed-effects models.ResultsFollowing CS-6253 intravenous injection, within minutes, small plasma high-density lipoprotein (HDL) particles were increased. In two independent experiments, plasma TG, apolipoprotein E (apoE), and Aβ42/40 ratio were transiently increased following CS-6253 intravenous injection. This change was associated with a non-significant decrease in CSF Aβ42. Both plasma total cholesterol and HDL-cholesterol levels were reduced following treatment. AF4 fractionation revealed that CS-6253 treatment displaced apoE from HDL to intermediate-density- and low density-lipoprotein (IDL/LDL)-sized particles in plasma. In contrast to plasma, CS-6253 had no effect on the assessed CSF apolipoproteins or lipids.ConclusionsTreatment with the ABCA1 agonist CS-6253 appears to favor Aβ clearance from the brain.

Phytochemical and Pharmacological Screening of Salvia Hispanica Seed Extracts against Alzeimer’s Disease in Rodents

The objective of this study was to identify the potential of salvia hispanica as protective and therapeutic agent against Alzheimer’s disease. The learning and memory enhancing activity of saliva hispanica seed extract were investigated in rats by using the ethanol induced cognitive impairment and diazepam induced amnesia and its effects on learning and memory were examined by using Morris water maze (MWM) test and 8-radial arm maze (8-RAM) test. For Morris water maze test all groups showed significantly (P value is < 0.01 &< 0.05) decreases transfer latency time at all periods as compared to ethanol and diazepam inducing group & for radial arm maze test all groups showed significantly (P value is< 0.0001) decreased in the time taken to reach the paired arm and number of entries in baited arm and non-baited arm as compared to ethanol inducing group. Therefore seed extracts of salvia hispanica exhibited significantly learning and memory activity in Alzheimer’s disease.

Phytochemical Screening and Learning and Memory Activity of Cucurbita pepo against Ethanol Induced Cognitive Impairment in Rodents by Using 8-ARM Radial Maze [8-ARM

The present study was undertaken to investigate the learning and memory enhancing activity of Cucurbita pepo seed extract in rats by using the ethanol induced cognitive impairment and its effects were examined by using 8-radial arm maze (8-RAM) test. For radial arm maze test all groups showed significantly (P value is< 0.0001& < 0.001) decreased in the time taken to reach the paired arm and number of entries in baited arm and non-baited arm as compared to ethanol inducing group. Therefore seed extracts of Cucurbita pepo exhibited significantly learning and memory activity in Alzheimer’s disease.

Effect of ginkgolide K on calcium channel activity in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative dementia with the key pathological hallmark of amyloid deposits that may induce mitochondrial dysfunction. Ginkgolide K (GK) has been proven to have neuroprotective effects. The present study sought to explore the neuroprotective effect of GK through regulation of the expression of mitochondrial Ca2+ uniporter (MCU) in the pathology of AD. SH-SY5Y cells were cultured and the expression of MCU was enhanced by transfection of MCU recombinant vectors or knockdown by MCU small interfering RNA. The cells were treated with GK and amyloid β (Aβ). Thereafter, the effects of GK, MCU expression and Aβ on viability and apoptosis of SH-SY5Y cells were examined via a WST-1 assay, flow cytometry and Caspase-3/8 activity assays, respectively. The effects of GK, MCU expression and Aβ on the calcium levels in mitochondria were also examined. The regulatory effect of GK on MCU expression was examined by reverse transcription-quantitative PCR and western blot analysis. Furthermore, APP/PS1 mice received supplementation with GK and their cognitive ability was then examined through water maze tests, while the expression of MCU was examined using immunohistochemistry. The results indicated that enhancing the expression of MCU inhibited cell viability and promoted apoptosis. GK protected cells from amyloid-induced cytotoxicity by promoting cell viability and preventing cell apoptosis. The neuroprotective effect of GK was abolished when MCU expression was knocked down. GK decreased the expression of MCU in vitro and downregulation of MCU decreased the calcium level in mitochondria. Treatment with GK in APP/PS1 mice downregulated the expression of MCU in the brains and alleviated cognitive impairment. In conclusion, the present study demonstrated that the administration of GK protected neurons by preventing apoptosis. Furthermore, the neuroprotective effect of GK in neuronal cells was indicated to be related to the inhibition of MCU expression. Therefore, administration of GK may be a promising strategy for treating AD.

α-mangostin derivative 4e as a PDE4 inhibitor promote proteasomal degradation of alpha-synuclein in Parkinson's disease models through PKA activation

BackgroundParkinson's disease (PD) is a multi-factorial neurodegenerative disease affecting motor function of patients. The hall markers of PD are dopaminergic neuron loss in the midbrain and the presence of intra-neuronal inclusion bodies mainly composed of aggregation-prone protein alpha-synuclein (α-syn). Ubiquitin-proteasome system (UPS) is a multi-step reaction process responsible for more than 80% intracellular protein degradation. Impairment of UPS function has been observed in the brain tissue of PD patients. PDE4 inhibitors have been shown to activate cAMP-PKA pathway and promote UPS activity in Alzheimer's disease model. α-mangostin is a natural xanthonoid with broad biological activities, such as antioxidant, antimicrobial and antitumour activities. Structure-based optimizations based on α-mangostin produced a potent PDE4 inhibitor, 4e. Herein, we studied whether 4e could promote proteasomal degradation of α-syn in Parkinson's disease models through PKA activation. MethodscAMP Assay was conducted to quantify cAMP levels in samples. Model UPS substrates (Ub-G76V-GFP and Ub-R-GFP) were used to monitor UPS-dependent activity. Proteasome activity was investigated by short peptide substrate, Suc-LLVY-AMC, cleavage of which by the proteasome increases fluorescence sensitivity. Tet-on WT, A30P, and A53T α-syn-inducible PC12 cells and primary mouse cortical neurons from A53T transgenic mice were used to evaluate the effect of 4e against α-syn in vitro. Heterozygous A53T transgenic mice were employed to assess the effect of 4e on the clearance of α-syn in vivo, and further validations were applied by western blotting and immunohistochemistry. ResultsTaken together, α-mangostin derivative 4e, a PDE4 inhibitor, efficiently activated the cAMP/PKA pathway in neuronal cells, and promoted UPS activity as evidenced by enhanced degradation of UPS substrate Ub-G76V-GFP and Ub-R-GFP, as well as elevated proteasomal enzyme activity. Interestingly, 4e dramatically accelerated degradation of inducibly-expressed WT and mutant α-syn in PC12 cells, in a UPS dependent manner. Besides, 4e consistently activated PKA in primary neuron and A53T mice brain, restored UPS inhibition and alleviated α-syn accumulation in the A53T mice brain. Conclusions4e is a natural compound derived highly potent PDE4 inhibitor. We revealed its potential effect in promoting UPS activity to degrade pathogenic proteins associated with PD.

The Significance of Subclinical Epileptiform Activity in Alzheimer's Disease: A Review.

Hyperexcitability is a recently recognized contributor to the pathophysiology of Alzheimer's disease (AD). Subclinical epileptiform activity (SEA) is a neurophysiological sign of cortical hyperexcitability; however, the results of the studies in this field vary due to differences in the applied methodology. The aim of this review is to summarize the results of the related studies aiming to describe the characteristic features and significance of subclinical epileptiform discharges in the pathophysiologic process of AD from three different directions: (1) what SEA is; (2) why we should diagnose SEA, and (3) how we should diagnose SEA. We scrutinized both the completed and ongoing antiepileptic drug trials in AD where SEA served as a grouping variable or an outcome measure. SEA seems to appear predominantly in slow-wave sleep and in the left temporal region and to compromise cognitive functions. We clarify using supportive literature the high sensitivity of overnight electroencephalography (EEG) in the detection of epileptiform discharges. Finally, we present the most important research questions around SEA and provide an overview of the possible solutions.

Antiviral, immunomodulatory, and neuroprotective effect of lithium.

Currently, in psychiatry, lithium is a drug of choice as a mood stabilizer in the maintenance treatment of bipolar disorder for the prevention of manic and depressive recurrences. The second most important psychiatric use of lithium is probably increasing the efficacy of antidepressants in treatment-resistant depression. In addition to its mood-stabilizing properties, lithium exerts antisuicidal, antiviral, immunomodulatory, and neuroprotective effects. The goal of the review is to describe the experimental and clinical studies on the last three properties of lithium. Antiviral effects of lithium pertain mostly to DNA viruses, especially herpes viruses. The therapeutic effects of lithium in systemic and topical administration on labial and genital herpes were demonstrated in clinical studies. There is also some evidence, mostly in experimental studies, that lithium possesses antiviral activity against RNA viruses, including coronaviruses. The immunomodulatory effect of lithium can mitigate "low-grade inflammatory" conditions in bipolar illness. The neuroprotective properties of lithium make this ion a plausible candidate for the prevention and treatment of neurodegenerative disorders. A favorable effect of lithium was shown in experimental models of neurodegenerative disorders. On the clinical level, some preventive action against dementia and moderately therapeutic activity in Alzheimer's disease, and mild cognitive impairment were observed. Despite promising results of lithium obtained in animal models of Huntington's disease and amyotrophic lateral sclerosis, they have not been confirmed in clinical studies. A suggestion for common mechanisms of antiviral, immunomodulatory, and neuroprotective effects of lithium is advanced.

Microglial activation in Alzheimer's disease: The role of flavonoids and microRNAs

Alzheimer's disease (AD) is the most common form of senile dementia and is characterized by progressive cognitive impairment and neuronal degeneration. Microglial activation is an important pathologic hallmark of AD. During disease progression, microglial cells switch from an alternative or anti-inflammatory and neuroprotective profile (M2) to a classic or proinflammatory and neurotoxic profile (M1). Phenotypically, M1 microglia is characterized by the activation of inflammatory signaling pathways that cause increased expression of proinflammatory genes, including those coding for cytokines and chemokines. This microglia-mediated neuroinflammation contributes to neuronal cell death. Recent studies in microglial cells have shown that a group of plant-derived compounds, known as flavonoids, possess anti-inflammatory properties and therefore exert a neuroprotective effect through regulating microglia activation. Here, we discuss how flavonoids can promote the switch from an inflammatory M1 phenotype to an anti-inflammatory M2 phenotype in microglia and how this represents a valuable opportunity for the development of novel therapeutic strategies to blunt neuroinflammation and boost neuronal recovery in AD. We also review how certain flavonoids can inhibit neuroinflammation through their action on the expression of microglia-specific microRNAs (miRNAs), which also constitute a key therapeutic approach in different neuropathologies involving an inflammatory component, including AD. Finally, we propose novel targets of microglia-specific miRNAs that may be considered for AD treatment.