Effects and mechanism of Aß1-42 on EV-A71 replication.

BACKGROUND: ß-Amyloid (Aß) protein is a pivotal pathogenetic factor in Alzheimer's disease (AD). However, increasing evidence suggests that the brain has to continuously produce excessive Aß to efficaciously prevent pathogenic micro-organism infections, which induces and accelerates the disease process of AD. Meanwhile, Aß exhibits activity against herpes simplex virus type 1 (HSV-1) and influenza A virus (IAV) replication, but not against other neurotropic viruses. Enterovirus A71 (EV-A71) is the most important neurotropic enterovirus in the post-polio era. Given the limitation of existing research on the relationship between Aß and other virus infections, this study aimed to investigate the potent activity of Aß on EV-A71 infection and extended the potential function of Aß in other unenveloped viruses may be linked to Alzheimer's disease or infectious neurological diseases. METHODS: Aß peptides 1-42 are a major pathological factor of senile plaques in Alzheimer's disease (AD). Thus, we utilized Aß1-42 as a test subject to perform our study. The production of monomer Aß1-42 and their high-molecular oligomer accumulations in neural cells were detected by immunofluorescence assay, ELISA, or Western blot assay. The inhibitory activity of Aß1-42 peptides against EV-A71 in vitro was detected by Western blot analysis or qRT-PCR. The mechanism of Aß1-42 against EV-A71 replication was analyzed by time-of-addition assay, attachment inhibition assay, pre-attachment inhibition analysis, viral-penetration inhibition assay, TEM analysis of virus agglutination, and pull-down assay. RESULTS: We found that EV-A71 infection induced Aß production and accumulation in SH-SY5Y cells. We also revealed for the first time that Aß1-42 efficiently inhibited the RNA level of EV-A71 VP1, and the protein levels of VP1, VP2, and nonstructural protein 3AB in SH-SY5Y, Vero, and human rhabdomyosarcoma (RD) cells. Mechanistically, we demonstrated that Aß1-42 primarily targeted the early stage of EV-A71 entry to inhibit virus replication by binding virus capsid protein VP1 or scavenger receptor class B member 2. Moreover, Aß1-42 formed non-enveloped EV-A71 particle aggregates within a certain period and bound to the capsid protein VP1, which partially caused Aß1-42 to prevent viruses from infecting cells. CONCLUSIONS: Our findings unveiled that Aß1-42 effectively inhibited nonenveloped EV-A71 by targeting the early phase of an EV-A71 life cycle, thereby extending the potential function of Aß in other non-envelope viruses linked to infectious neurological diseases.

Combined Modeling Study of the Binding Characteristics of Natural Compounds, Derived from Psoralea Fruits, to ß-Amyloid Peptide Monomer.

A dysfunctional protein aggregation in the nervous system can lead to several neurodegenerative disorders that result in intracellular inclusions or extracellular aggregates. An early critical event within the pathogenesis of Alzheimer's disease is the accumulation of amyloid beta peptide within the brain. Natural compounds isolated from Psoralea Fructus (PF) have significant anti-Alzheimer effects as strong inhibitors of Aß42 aggregation. Computer simulations provide a powerful means of linking experimental findings to nanoscale molecular events. As part of this research four prenylated compounds, the active ingredients of Psoralea Fructus (PF), were studied as Aß42 accumulation inhibitors using molecular simulations modeling. In order to resolve the binding modes of the ligands and identify the main interactions of Aß42 residues, we performed a 100 ns molecular dynamics simulation and binding free energy calculations starting from the model of the compounds obtained from the docking study. This study was able to pinpoint the key amino acid residues in the Aß42 active site and provide useful information that could benefit the development of new Aß42 accumulation inhibitors.

Not a piece of junk anymore: Pseudogene T04B2.1 performs non-conventional regulatory role and modulates aggregation of α- synuclein and ß-amyloid proteins in C. elegans.

The conventional notions of pseudogenes being 'junk DNA' have largely been offset as research studies have established their role in multiple biological processes. Our studies towards identification of genetic modulators employing C. elegans model, that associate reproductive health and age-related neurodegenerative diseases, led us to identification and functional characterization of a pseudogene T04B2.1, which when knocked down, exacerbates the aggregation of α-Synuclein and ß-Amyloid proteins, induces lipid deposition and alters morphometric endpoints in worms. Whole transcriptome analysis of worms under knockdown condition of T04B2.1 revealed an altered expression of 187 sequences, most of these being non-coding RNAs, miRNAs and piRNAs modulating the RNAi regulatory processes. Our gene ontology and pathway enrichment analysis demonstrated the role of T04B2.1 in protein quality control, metabolic pathways and development. We further performed a signature motif search and successfully identified a common motif that is present between all piRNA and miRNA molecules, which are significantly altered upon T04B2.1 silencing. This study unveils the non-conventional regulatory role of pseudogene T04B2.1 with respect to effects associated with neurodegenerative diseases and encourages further studies to decipher the regulatory mechanism governed by pseudogenes.

LRP1 knockdown aggravates Aß1-42-stimulated microglial and astrocytic neuroinflammatory responses by modulating TLR4/NF-κB/MAPKs signaling pathways.

Neuroinflammation is an important pathological feature and an early event in the pathogenesis of Alzheimer's disease (AD), which is characterized by activation of microglia and astrocytes. Low-density lipoprotein receptor-related protein 1 (LRP1) is an endocytic receptor that is abundantly expressed in neurons, microglia, and astrocytes, and plays a critical role in AD pathogenesis. There is increasing evidence to show that LRP1 regulates inflammatory responses by modulating the release of pro-inflammatory cytokines and phagocytosis. However, the effects of LRP1 on ß-amyloid protein (Aß)-induced microglial and astrocytic neuroinflammatory responses and its underlying mechanisms have not been studied in detail. In the present study, knockdown of LRP1 significantly enhanced Aß1-42-stimulated neuroinflammation by increasing the production of pro-inflammatory cytokines in both BV2 microglial cells and mouse primary astrocytes. Furthermore, it is revealed that LRP1 knockdown further led to the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways. The phosphorylation of IκBα, p38, and JNK was significantly up-regulated in LRP1 knockdown BV2 microglial cells and primary astrocytes. Meanwhile, LRP1 knockdown increased expression of the NF-κB p65 subunit in the nucleus while decreased its expression in the cytoplasm. Besides, the upstream signaling adaptor molecules such as toll-like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MyD88), and tumor necrosis factor receptor-associated factor 6 (TRAF6) were also further increased. Moreover, blockade of NF-κB, p38, and JNK inhibited the production of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) induced by the knockdown of LRP1. Taken together, these findings indicated that LRP1 as an effective therapeutic target against AD and other neuroinflammation related diseases.

In vitro neuroprotective effects of farnesene sesquiterpene on alzheimer's disease model of differentiated neuroblastoma cell line.

OBJECTIVE: To investigate neuroprotective properties of the farnesene sesquiterpene on the experimental Alzheimer's disease model in vitro. METHODS: Human neuroblastoma cell line (SHSY-5Y) was differentiated into neuron-like cells by using retinoic acid to constitute the in vitro Alzheimer's Disease model. ß-amyloid 1-42 protein was applied to the transformed cells for 24 and 48 hours in a wide dose ranges (3.125-200 µM) to establish AD cytotoxicity. Then, farnesene was applied to cell cultures in a wide spectrum dose interval (1.625-100 µg/ml) to investigate neuroprotective effect against ß-amyloid for 24 and 48 hours. 3-(4,5-dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release tests were executed to determine cytotoxicity in the Alzheimer model. Nuclear DNA integrity of cells was examined under the fluorescent microscope using the Hoechst 33258 staining method. Furthermore, acetylcholinesterase (AChE) activity, total antioxidant capacity (TAC) and total oxidative status (TOS) levels were analyzed to understand the protection mechanism of the farnesene application on the cell culture model. Finally, flow cytometry analysis was used to find out the cell death mechanism after beta-amyloid and farnesene application to the cell culture. RESULTS: Cell viability tests revealed significant neuroprotection against ß-amyloid toxicity in both 24 and 48 hours and the Hoechst 33258 fluorescence staining method showed a significant decrease in necrotic deaths after farnesene application in the cell cultures. Finally, flow cytometry analysis put forth that farnesene could decrease necrotic cell death up to 3-fold resulted from beta-amyloid exposure. CONCLUSION: According to the investigations, farnesene can potentially be a safe, anti-necrotic and neuroprotective agents against Alzheimer's disease.

Indomethacin Disrupts the Formation of ß-Amyloid Plaques via an α2-Macroglobulin-Activating lrp1-Dependent Mechanism.

Epidemiological studies have implied that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the development and progression of Alzheimer's disease (AD). However, the underlying mechanisms are notably understudied. Using a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) (APP/PS1) expressing transgenic (Tg) mice and neuroblastoma (N) 2a cells as in vivo and in vitro models, we revealed the mechanisms of indomethacin in ameliorating the cognitive decline of AD. By screening AD-associated genes, we observed that a marked increase in the expression of α2-macroglobulin (A2M) was markedly induced after treatment with indomethacin. Mechanistically, upregulation of A2M was caused by the inhibition of cyclooxygenase-2 (COX-2) and lipocalin-type prostaglandin D synthase (L-PGDS), which are responsible for the synthesis of prostaglandin (PG)H2 and PGD2, respectively. The reduction in PGD2 levels induced by indomethacin alleviated the suppression of A2M expression through a PGD2 receptor 2 (CRTH2)-dependent mechanism. Highly activated A2M not only disrupted the production and aggregation of ß-amyloid protein (Aß) but also induced Aß efflux from the brain. More interestingly, indomethacin decreased the degradation of the A2M receptor, low-density lipoprotein receptor-related protein 1 (LRP1), which facilitated the brain efflux of Aß. Through the aforementioned mechanisms, indomethacin ameliorated cognitive decline in APP/PS1 Tg mice by decreasing Aß production and clearing Aß from the brains of AD mice.

Nitrogen-Doped Carbonized Polymer Dots: A Potent Scavenger and Detector Targeting Alzheimer's ß-Amyloid Plaques.

The fibrillization and deposition of ß-amyloid protein (Aß) are recognized to be the pathological hallmarks of Alzheimer's disease (AD), which signify the need for the effective detection and inhibition of Aß accumulation. Development of multifunctional agents that can inhibit Aß aggregation, rapidly disaggregate fibrils, and image aggregates is one of the effective strategies to treat and diagnose AD. Herein, the multifunctionality of nitrogen-doped carbonized polymer dots (CPDs) targeting Aß aggregation is reported. CPDs inhibit the fibrillization of Aß monomers and rapidly disintegrate Aß fibrils by electrostatic interactions, hydrogen-bonding and hydrophobic interactions with Aß in a time scale of seconds to minutes. Moreover, the interactions make CPDs label Aß fibrils and emit enhanced red fluorescence by the binding, so CPDs can be used for in vivo imaging of the amyloids in transgenic Caenorhabditis elegans CL2006 as an AD model. Importantly, CPDs are demonstrated to scavenge the in vivo amyloid plaques and to promote the lifespan extension of CL2006 strain by alleviating the Aß-triggered toxicity. Taken together, the multifunctional CPDs show an exciting prospect for further investigations in Aß-targeted AD treatment and diagnosis, and this study provides new insight into the development of carbon materials in AD theranostics.

CGA restrains the apoptosis of Aß25-35-induced hippocampal neurons.

Background: Chlorogenic acid (CGA) has anti-oxidant and anti-inflammatory effects, but the study on its role in Alzheimer's disease (AD) models remains rare. Here, the effects of CGA on ß-amyloid protein (Aß)-induced cell models were investigated, aiming to provide a direction for Aß-induced AD.Material and methods: Hippocampal neurons were separated from newborn Sprague-Dawley (SD) rats and identified by immumofluorescence method. Hippocampal neurons were processed with Aß25-35 after pre-treatment CGA. MTT assay was used for detecting viability of treated cells. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA) and lactate dehydrogenase (LDH) of treated hippocampal neurons were determined by corresponding kits. Flow cytometry analysis assessed the apoptosis and mitochondrial membrane potential (MMP) in hippocampal neurons after treatment. The expressions of proteins related to apoptosis and endoplasmic reticulum stress (ERS) were measured by western blot (WB) analysis.Results: Immumofluorescence method showed that the Aß25-35 induction models were successfully constructed. CGA increased the viability and decreased the apoptosis rate of Aß25-35-induced hippocampal neurons. Decreasing activities of LDH and MDA, and raised contents of SOD and GSH-Px were appeared in Aß25-35-induced cells that pre-treated with CGA. Moreover, CGA also enhanced MMP intensity of hippocampal neurons induced by Aß25-35. In WB analysis, CGA reversed the promoting effect of Aß25-35 on the expressions of proteins related to pro-ERS and pro-apoptosis.Conclusion: CGA restrained the apoptosis of Aß25-35-induced hippocampal neurons via improving the anti-oxidant capacity, mitochondrial injury and ERS state of cells, which may provide a direction for AD.

Prodromal Intestinal Events in Alzheimer's Disease (AD): Colonic Dysmotility and Inflammation Are Associated with Enteric AD-Related Protein Deposition.

Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer's disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age. In vitro colonic motility was examined. Faecal and colonic Aß, tau proteins, α-synuclein and IL-1ß were assessed by ELISA. Colonic citrate synthase activity was assessed by spectrophotometry. Colonic NLRP3, caspase-1 and ASC expression were evaluated by Western blotting. Colonic eosinophil density and claudin-1 expression were evaluated by immunohistochemistry. The effect of Aß on NLRP3 signalling and mitochondrial function was tested in cultured cells. Cognitive impairment and decreased faecal output occurred in SAMP8 mice from six months. When compared with SAMR1, SAMP8 animals displayed: (1) impaired in vitro colonic contractions; (2) increased enteric AD-related proteins, IL-1ß, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, Aß promoted IL-1ß release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC-/- cells. Aß decreased mitochondrial function in THP-1 cells. In SAMP8, enteric AD-related proteins deposition, inflammation and impaired colonic excitatory neurotransmission, occurring before the full brain pathology development, could contribute to bowel dysmotility and represent prodromal events in AD.

Synaptic plasticity modulation by circulating peptides and metaplasticity: Involvement in Alzheimer's disease.

Synaptic plasticity is a cellular process involved in learning and memory whose alteration in its two main forms (Long Term Depression (LTD) and Long Term Potentiation (LTP)), is observed in most brain pathologies, including neurodegenerative disorders such as Alzheimer's disease (AD). In humans, AD is associated at the cellular level with neuropathological lesions composed of extracellular deposits of ß-amyloid (Aß) protein aggregates and intracellular neurofibrillary tangles, cellular loss, neuroinflammation and a general brain homeostasis dysregulation. Thus, a dramatic synaptic environment perturbation is observed in AD patients, involving changes in brain neuropeptides, cytokines, growth factors or chemokines concentration and diffusion. Studies performed in animal models demonstrate that these circulating peptides strongly affect synaptic functions and in particular synaptic plasticity. Besides this neuromodulatory action of circulating peptides, other synaptic plasticity regulation mechanisms such as metaplasticity are altered in AD animal models. Here, we will review new insights into the study of synaptic plasticity regulatory/modulatory mechanisms which could influence the process of synaptic plasticity in the context of AD with a particular attention to the role of metaplasticity and peptide dependent neuromodulation.

Mithramycin A Alleviates Cognitive Deficits and Reduces Neuropathology in a Transgenic Mouse Model of Alzheimer's Disease.

Increasing evidence has shown that specificity protein 1 (Sp1) is abnormally increased in the brains of subjects with Alzheimer's disease (AD) and transgenic AD models. However, whether the Sp1 activation plays a critical role in the AD pathogenesis and selective inhibition of Sp1 activation may have a disease-modifying effect on the AD-like phenotypes remain elusive. In this study, we reported that Sp1 mRNA and protein expression were markedly increased in the brain of APPswe/PS1dE9 transgenic mice, whereas chronic administration of mithramycin A (MTM), a selective Sp1 inhibitor, potently inhibited Sp1 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, we found that MTM treatment resulted in a significant improvement of learning and memory deficits, a dramatic reduction in cerebral Aß levels and plaque burden, a profound reduction in tau hyperphosphorylation, and a marked increase in synaptic marker in the APPswe/PS1dE9 mice. In addition, MTM treatment was powerfully effective in inhibiting amyloid precursor protein (APP) processing via suppressing APP, beta-site APP cleaving enzyme 1 (BACE1), and presenilin-1 (PS1) mRNA and protein expression to preclude Aß production in the APPswe/PS1dE9 mice. Furthermore, MTM treatment strongly inhibited phosphorylated CDK5 and GSK3ß signal pathways to reduce tau hyperphosphorylation in the APPswe/PS1dE9 mice. Collectively, our findings provide evidence that Sp1 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD. The present study highlights that selective Sp1 inhibitors may be considered as disease-modifying therapeutic agents for AD.

Microdosing of scopolamine as a "cognitive stress test": rationale and test of a very low dose in an at-risk cohort of older adults.

BACKGROUND: Abnormal ß-amyloid (Aß) is associated with deleterious changes in central acetylcholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist. We aimed to establish an optimal "microdose" of scopolamine for the development of a "cognitive stress test." METHODS: Healthy older adults (n = 26, aged 55-75 years) with two risk factors for AD, but with low cortical Aß burden, completed the Groton Maze Learning Test (GMLT) at baseline and then received scopolamine (0.20 mg subcutaneously). Participants were reassessed at 1, 3, 5, 7, and 8 hours postinjection. RESULTS: There were significant differences, of a moderate magnitude, in performance between baseline and 3 hours postinjection for total errors, rule break errors, and the GMLT composite (d ≈ 0.50) that were all unrelated to body mass. CONCLUSIONS: A very low dose of scopolamine leads to reliable cognitive impairment at 3 hours postdose (Tmax) and full cognitive recovery within 5 hours, supporting its use as a prognostic test paradigm to identify individuals with potential preclinical AD. This paradigm is being implemented in a larger cohort of healthy adults, with high or low Aß, to identify pharmacodynamic differences between groups.

Quercetin-derived red emission carbon dots: A multifunctional theranostic nano-agent against Alzheimer's ß-amyloid fibrillogenesis.

Multifunctional agents with therapeutic and diagnostic capabilities are imperative to the prevention of Alzheimer's disease (AD), which is considered due to abnormal aggregation and deposition of ß-amyloid protein (Aß) as well as oxidative stress. Herein, quercetin (Que)- and p-phenylenediamine (p-PD)-derived red emission carbon dots (CDs) synthesized via a one-step hydrothermal method were designed as a novel theranostic nano-agent for the multi-target treatment of AD. R-CD-75 with an optimized composition exhibited significant inhibition of Aß aggregation and rapid depolymerization of mature Aß fibrils (<4 h) at micromolar concentrations (2 and 5 µg/mL, respectively). Moreover, R-CD-75 potently scavenged reactive oxygen species and showed turned-on red fluorescence imaging of Aß plaques both in vitro and in vivo. In vitro assays proved that R-CD-75 significantly mitigated the Aß-induced cytotoxicity and enhanced the cultured cell viability from 74.9 % to 98.0 %, while in vivo studies demonstrated that R-CD-75 prolonged the lifespan of AD nematodes by over 50 % (from 13 to 20 d). Compared to the precursors Que and p-PD, R-CD-75 inherited some of their structures and functional groups, such as aromatic structures, phenolic hydroxyl and amino groups, which were considered to interact with Aß species through hydrogen bonding, electrostatic interactions, hydrophobic interactions, and π-π stacking, thus contributing to its effectiveness in its theranostic functions. This research has opened a new avenue to the development of potent theranostic agents by designing novel carbon dots.

Selective Orexin 2 Receptor Blockade Alleviates Cognitive Impairments and the Pathological Progression of Alzheimer's Disease in 3xTg-AD Mice.

The orexin system is closely related to the pathogenesis of Alzheimer's disease (AD). Orexin-A aggravates cognitive dysfunction and increases amyloid ß (Aß) deposition in AD model mice, but studies of different dual orexin receptor (OXR) antagonists in AD have shown inconsistent results. Our previous study revealed that OX1R blockade aggravates cognitive deficits and pathological progression in 3xTg-AD mice, but the effects of OX2R and its potential mechanism in AD have not been reported. In the present study, OX2R was blocked by oral administration of the selective OX2R antagonist MK-1064, and the effects of OX2R blockade on cognitive dysfunction and neuropsychiatric symptoms in 3xTg-AD mice were evaluated via behavioral tests. Then, immunohistochemistry, western blotting, and ELISA were used to detect Aß deposition, tau phosphorylation, and neuroinflammation, and electrophysiological and wheel-running activity recording were recorded to observe hippocampal synaptic plasticity and circadian rhythm. The results showed that OX2R blockade ameliorated cognitive dysfunction, improved LTP depression, increased the expression of PSD-95, alleviated anxiety- and depression-like behaviors and circadian rhythm disturbances in 3xTg-AD mice, and reduced Aß pathology, tau phosphorylation, and neuroinflammation in the brains of 3xTg-AD mice. These results indicated that chronic OX2R blockade exerts neuroprotective effects in 3xTg-AD mice by reducing AD pathology at least partly through improving circadian rhythm disturbance and the sleep-wake cycle and that OX2R might be a potential target for the prevention and treatment of AD; however, the potential mechanism by which OX2R exerts neuroprotective effects on AD needs to be further investigated.

Serum albumin-embedding copper nanoclusters inhibit Alzheimer's ß-amyloid fibrillogenesis and neuroinflammation.

Increasing evidence suggests that the accumulations of reactive oxygen species (ROS), ß-amyloid (Aß), and neuroinflammation are crucial pathological hallmarks for the onset of Alzheimer's disease (AD), yet there are few effective treatment strategies. Therefore, design of nanomaterials capable of simultaneously elimination of ROS and inhibition of Aß aggregation and neuroinflammation is urgently needed for AD treatment. Herein, we designed human serum albumin (HSA)-embedded ultrasmall copper nanoclusters (CuNCs@HSA) via an HSA-mediated fabrication strategy. The as-prepared CuNCs@HSA exhibited outstanding multiple enzyme-like properties, including superoxide dismutase (>5000 U/mg), catalase, and glutathione peroxidase activities as well as hydroxyl radicals scavenging ability. Besides, CuNCs@HSA prominently inhibited Aß fibrillization, and its inhibitory potency was 2.5-fold higher than native HSA. Moreover, CuNCs@HSA could significantly increase the viability of Aß-treated cells from 60 % to over 96 % at 40 µg/mL and mitigate Aß-induced oxidative stresses. The secretion of neuroinflammatory cytokines by lipopolysaccharide-induced BV-2 cells, including tumor necrosis factor-α and interleukin-6, was alleviated by CuNCs@HSA. In vivo studies manifested that CuNCs@HSA effectively suppressed the formation of plaques in transgenic C. elegans, reduced ROS levels, and extended C. elegans lifespan by 5 d. This work, using HSA as a template to mediate the fabrication of copper nanoclusters with robust ROS scavenging capability, exhibited promising potentials in inhibiting Aß aggregation and neuroinflammation for AD treatment.

Macrophage Membrane-Modified MoS2 Quantum Dots as a Nanodrug for Combined Multi-Targeting of Alzheimer's Disease.

The complex pathological mechanism of Alzheimer's disease (AD) limits the efficacy of simple drug therapy, and drugs are difficult to penetrate the blood-brain barrier (BBB). Therefore, it is a breakthrough to enhance the therapeutic effect of AD by rationally using multiple therapeutic strategies to inhibit multiple pathological targets. In this study, macrophage membrane (MM) with active targeting inflammation function is used to functionalize molybdenum disulfide quantum dots (MoS2 QDs) with the properties of elimination of reactive oxygen species (ROS) and anti-Aß1-42 deposition to form the nano drug (MoS2 QDs/MM), and play the role of multi-target combined therapy with NIR. The results show that MoS2 QDs/MM has a targeted therapeutic effect on ROS elimination and anti-deposition of Aß1-42 . In addition, the combined therapy group effectively reduced Aß1-42 mediated cytotoxicity. The modification of MM could effectively target the brain, and NIR irradiation could actively increase the cross of BBB of materials. In vivo behavioral study also show that APP/PS1 mice in the combined treatment group showed the similar exploration desire and learning ability to mice in the group of WT. MoS2 QDs/MM is an excellent nano drug with multiple effects, which has advantages in the field of neurological diseases with crisscross pathogenesis.

Association Between Clonal Hematopoiesis of Indeterminate Potential and Brain ß-Amyloid Deposition in Korean Patients With Cognitive Impairment.

Few studies have focused on the association between clonal hematopoiesis of indeterminate potential (CHIP) and ß-amyloid (Aß) deposition in the brain, which causes Alzheimer's disease. We aimed to investigate the potential role of CHIP in brain Aß deposition in Korean patients. We enrolled 58 Korean patients over 50 yrs of age with cognitive impairment who underwent brain Aß positron emission tomography. We explored CHIP in their peripheral blood using deep-targeted next-generation sequencing. Irrespective of the presence or absence of brain Aß deposition, mutations in DNMT3A and the C:G>T:A single-nucleotide variants were identified as the primary characteristics, which reflect aged hematopoiesis in the study population. Multivariate logistic regression revealed that the presence of CHIP was not associated with brain Aß deposition. As both CHIP and brain Aß deposition are associated with aging, further research is required to elucidate their possible interplay.

True or false? Alzheimer's disease is type 3 diabetes: Evidences from bench to bedside.

Globally, Alzheimer's disease (AD) is the most widespread chronic neurodegenerative disorder, leading to cognitive impairment, such as aphasia and agnosia, as well as mental symptoms, like behavioral abnormalities, that place a heavy psychological and financial burden on the families of the afflicted. Unfortunately, no particular medications exist to treat AD, as the current treatments only impede its progression.The link between AD and type 2 diabetes (T2D) has been increasingly revealed by research; the danger of developing both AD and T2D rises exponentially with age, with T2D being especially prone to AD. This has propelled researchers to investigate the mechanism(s) underlying this connection. A critical review of the relationship between insulin resistance, Aß, oxidative stress, mitochondrial hypothesis, abnormal phosphorylation of Tau protein, inflammatory response, high blood glucose levels, neurotransmitters and signaling pathways, vascular issues in AD and diabetes, and the similarities between the two diseases, is presented in this review. Grasping the essential mechanisms behind this detrimental interaction may offer chances to devise successful therapeutic strategies.

Effects of pressing moxibustion at Baihui (GV 20) and Guanyuan (CV 4) on cognitive impairment and serum levels of Aß1-42, tau, P-tau in patients with mild to moderate Alzheimer's disease. / åŽ‹ç¸ç™¾ä¼šã€å ³å ƒå¯¹è½»ä¸­åº¦é˜¿å°”èŒ¨æµ·é»˜ç— æ‚£è€ è®¤çŸ¥éšœç¢åŠè¡€æ¸ Aß1-42、tau、P-tau水平的影响.

OBJECTIVES: To compare the effects of pressing moxibustion at Baihui (GV 20) and Guanyuan (CV 4) combined with donepezil hydrochloride tablets and donepezil hydrochloride tablets alone on cognitive impairment in patients with mild to moderate Alzheimer's disease(AD), and to explore the mechanism of pressing moxibustion in the treatment of mild to moderate AD from the serum levels of ß-amyloid 1-42 (Aß1-42), microtubule-associated protein tau and phosphorylated tau (P-tau). METHODS: A total of 76 patients with mild to moderate AD were randomly divided into an observation group (38 cases, 4 cases dropped out) and a control group (38 cases, 2 cases dropped out). Patients in the control group were given oral donepezil hydrochloride tablets (5 mg each time, once a day). On the basis of the control group, patients in the observation group were treated with pressing moxibustion at Baihui (GV 20) and Guanyuan (CV 4), 5 cones per acupoint, once every other day, three times a week. Both groups were treated for 8 weeks. The scores of mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) were compared between the two groups before treatment, after treatment and after 4 and 12 weeks of treatment completion. The serum levels of Aß1-42, tau and P-tau were detected before and after treatment in the two groups, and the safety was evaluated. RESULTS: At each time point after treatment, the MMSE and MoCA scores of the two groups were higher than those before treatment (P<0.05), and the scores in the observation group were higher than those in the control group (P<0.05). After treatment, the serum levels of Aß1-42, tau and P-tau in the two groups were lower than those before treatment (P<0.05), and above indexes in the observation group were lower than those in the control group (P<0.05). There was no significant difference in the safety level between the two groups (P>0.05). CONCLUSIONS: The short-term and long-term effect of pressing moxibustion at Baihui (GV 20) and Guanyuan (CV 4) combined with donepezil hydrochloride tablets in improving cognitive impairment in mild to moderate AD is better than that of donepezil hydrochloride tablets alone, and can reduce serum levels of Aß1-42, tau and P-tau, which may be one of the mechanisms of pressing moxibustion to improve cognitive impairment.

Effects of antiparkinsonian agents on ß-amyloid and α-synuclein oligomer formation in vitro.

The aggregation of ß-amyloid protein (Aß) and α-synuclein (αS) are hypothesized to be the key pathogenic event in Alzheimer's disease (AD) and Lewy body diseases (LBD), with oligomeric assemblies thought to be the most neurotoxic. Inhibitors of oligomer formation, therefore, could be valuable therapeutics for patients with AD and LBD. Here, we examined the effects of antiparkinsonian agents (dopamine, levodopa, trihexyphenidyl, selegiline, zonisamide, bromocriptine, peroxide, ropinirole, pramipexole, and entacapone) on the in vitro oligomer formation of Aß40, Aß42, and αS using a method of photo-induced cross-linking of unmodified proteins (PICUP), electron microscopy, and atomic force microscopy. The antiparkinsonian agents except for trihexyphenidyl inhibited both Aß and αS oligomer formations, and, among them, dopamine, levodopa, pramipexole, and entacapone had the stronger in vitro activity. Circular dichroism and thioflavin T(S) assays showed that secondary structures of Aß and αS assemblies inhibited by antiparkinsonian agents were statistical coil state and that their seeding activities had disappeared. The antiparkinsonian agents could be potential therapeutic agents to prevent or delay AD and LBD progression.