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.

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.

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.

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.

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.

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.

Methylene Blue-Doped Carbonized Polymer Dots: A Potent Photooxygenation Scavenger Targeting Alzheimer's ß-Amyloid.

The abnormal aggregation of ß-amyloid protein (Aß) is one of the main pathological hallmarks of Alzheimer's disease (AD), and thus development of potent scavengers targeting Aß is considered an effective strategy for AD treatment. Herein, photosensitizer-doped carbonized polymer dots (PS-CPDs) were synthesized by a one-step hydrothermal method using photosensitizer (PS) and o-phenylenediamine (oPD) as precursors, and furtherly applied to inhibit Aß aggregation via photooxygenation. The inhibition efficiency of such PS-CPDs can be adjusted by varying the type of photosensitizer, and among them, methylene blue-doped carbonized polymer dots (MB-CPDs) showed the strongest photooxygenation inhibition capability. The results demonstrated that under 650 nm NIR light irradiation, MB-CPDs (2 µg/mL) produced reactive oxygen species (ROS) to efficiently inhibit Aß fibrillization and disaggregate mature Aß fibrils and increased the cultured cell viability from 50% to 83%. In vivo studies confirmed that MB-CPDs extended the lifespan of AD nematodes by 4 days. Notably, the inhibitory capability of MB-CPDs is much stronger than that of MB and previously reported carbonized polymer dots. This work indicated that potent photooxygenation carbon dots can be obtained by using a photosensitizer as one of the precursors, and the results have provided new insights into the design of potent photooxygenation carbon nanomaterials targeting Aß in AD treatment.

Preferential Regulation of Γ-Secretase-Mediated Cleavage of APP by Ganglioside GM1 Reveals a Potential Therapeutic Target for Alzheimer's Disease.

A hallmark of Alzheimer's disease (AD) is the senile plaque, which contains ß-amyloid peptides (Aß). Ganglioside GM1 is the most common brain ganglioside. However, the mechanism of GM1 in modulating Aß processing is rarely known. Aß levels are detected by using Immunohistochemistry (IHC) and enzyme-linked immune-sorbent assay (ELISA). Cryo-electron microscopy (Cryo-EM) is used to determine the structure of γ-secretase supplemented with GM1. The levels of the cleavage of amyloid precursor protein (APP)/Cadherin/Notch1 are detected using Western blot analysis. Y maze, object translocation, and Barnes maze are performed to evaluate cognitive functions. GM1 leads to conformational change of γ-secretase structure and specifically accelerates γ-secretase cleavage of APP without affecting other substrates including Notch1, potentially through its interaction with the N-terminal fragment of presenilin 1 (PS1). Reduction of GM1 levels decreases amyloid plaque deposition and improves cognitive dysfunction. This study reveals the mechanism of GM1 in Aß generation and provides the evidence that decreasing GM1 levels represents a potential strategy in AD treatment. These results provide insights into the detailed mechanism of the effect of GM1 on PS1, representing a step toward the characterization of its novel role in the modulation of γ-secretase activity and the pathogenesis of AD.

Folate Deficiency Increased Microglial Amyloid-ß Phagocytosis via the RAGE Receptor in Chronic Unpredictable Mild-Stress Rat and BV2 Cells.

Depression is often considered one of the prevalent neuropsychiatric symptoms of Alzheimer's disease (AD). ß-amyloid (Aß) metabolism disorders and impaired microglia phagocytosis are potential pathological mechanisms between depression and AD. Folate deficiency (FD) is a risk factor for depression and AD. In this study, we used a chronic unpredictable mild stress (CUMS) rat model and a model of Aß phagocytosis by BV2 cells to explore the potential mechanisms by which FD affects depression and AD. The results revealed that FD exacerbated depressive behavior and activated microglia in CUMS rats, leading to an increase in intracellular Aß and phagocytosis-related receptors for advanced glycation end products (RAGE). Then, in vitro results showed that the expression of the RAGE receptor and M2 phenotype marker (CD206) were upregulated by FD treatment in BV2 cells, leading to an increase in Aß phagocytosis. However, there was no significant difference in the expression of toll-like receptor 4 (TLR4) and clathrin heavy chain (CHC). Furthermore, when using the RAGE-specific inhibitor FPS-ZM1, there was no significant difference in Aß uptake between folate-normal (FN) and FD BV2 cell groups. In conclusion, these findings suggest FD may promote microglia phagocytosis Aß via regulating the expression of RAGE or microglia phenotype under Aß treatment.

Isolation of Fucoxanthin from Sargassum oligocystum Montagne, 1845 Seaweed in Vietnam and Its Neuroprotective Activity.

Fucoxanthin extracted and purified from Vietnamese Sargassum oligocystum Montagne, 1845 exhibits various biological activities. In this study, the ability of fucoxanthin to inhibit acetylcholinesterase (AChE), the antioxidant activities, and the expression of antioxidant enzymes were investigated. Fucoxanthin isolated from Vietnamese S. oligocystum showed no cytotoxic effects; moreover, it exhibited AChE inhibitory activity (with an IC50 value of 130.12 ± 6.65 µg mL-1) and antioxidant activity (with an IC50 value of 3.42 ± 0.15 mg mL-1). At concentrations of 50 and 100 µg mL-1, fucoxanthin provided protection against amyloid ß-protein fragment 25-35-induced neurotoxicity in a C6 neuronal cell line, and the survival of C6 cells was higher than 81.01% and 80.98%, respectively, compared to the control group (59%). Moreover, antioxidant enzyme activity and quantitative PCR analysis suggested that the neuroprotective effect of fucoxanthin resulted from regulation of the gene expression of antioxidant enzymes (CAT and GPx) and ER pathways (caspase-3 and Bax), as well as the promotion of expression of genes involved in PI3K/Akt signaling (GSK-3ß), autophagy (p62 and ATG5), and the biosynthesis of ACh (VAChT and ChAT). Therefore, fucoxanthin extracted from the seaweed S. oligocystum in Vietnam is a potential feedstock source for the production of health foods that exert neuroprotective effects.

Current and future therapeutic strategies for Alzheimer's disease: an overview of drug development bottlenecks.

Alzheimer's disease (AD) is the most common chronic neurodegenerative disease worldwide. It causes cognitive dysfunction, such as aphasia and agnosia, and mental symptoms, such as behavioral abnormalities; all of which place a significant psychological and economic burden on the patients' families. No specific drugs are currently available for the treatment of AD, and the current drugs for AD only delay disease onset and progression. The pathophysiological basis of AD involves abnormal deposition of beta-amyloid protein (Aß), abnormal tau protein phosphorylation, decreased activity of acetylcholine content, glutamate toxicity, autophagy, inflammatory reactions, mitochondria-targeting, and multi-targets. The US Food and Drug Administration (FDA) has approved five drugs for clinical use: tacrine, donepezil, carbalatine, galantamine, memantine, and lecanemab. We have focused on the newer drugs that have undergone clinical trials, most of which have not been successful as a result of excessive clinical side effects or poor efficacy. Although aducanumab received rapid approval from the FDA on 7 June 2021, its long-term safety and tolerability require further monitoring and confirmation. In this literature review, we aimed to explore the possible pathophysiological mechanisms underlying the occurrence and development of AD. We focused on anti-Aß and anti-tau drugs, mitochondria-targeting and multi-targets, commercially available drugs, bottlenecks encountered in drug development, and the possible targets and therapeutic strategies for future drug development. We hope to present new concepts and methods for future drug therapies for AD.

Protective Role of an Extract Waste Product from Citrus bergamia in an In Vitro Model of Neurodegeneration.

A balanced diet, rich in fruits and vegetables and ensuring the intake of natural products, has been shown to reduce or prevent the occurrence of many chronic diseases. However, the choice to consume large quantities of fruits and vegetables leads to an increase in the amount of waste, which can cause an alteration in environmental sustainability. To date, the concept of a "byproduct" has evolved, now being understood as a waste product from which it is still possible obtain useful compounds. Byproducts in the agricultural sector are a rich source of bioactive compounds, capable of possessing a second life, decreasing the amount of waste products, the disposal costs, and environmental pollution. A promising and well-known citrus of the Mediterranean diet is the bergamot (Citrus bergamia, Risso et Poiteau). The composition of bergamot is known, and the rich presence of phenolic compounds and essential oils has justified the countless beneficial properties found, including anti-inflammatory, antioxidant, anti-cholesterolemic, and protective activity for the immune system, heart failure, and coronary heart diseases. The industrial processing of bergamot fruits leads to the formation of bergamot juice and bergamot oil. The solid residues, referred to as "pastazzo", are normally used as feed for livestock or pectin production. The fiber of bergamot (BF) can be obtained from pastazzo and could exert an interesting effect thanks to its content of polyphenols. The aims of this work were twofold: (a) to have more information (composition, polyphenol and flavonoid content, antioxidant activity, etc.) on BF powder and (b) to verify the effects of BF on an in vitro model of neurotoxicity induced by treatment with amyloid beta protein (Aß). In particular, a study of cell lines was carried out on both neurons and oligodendrocytes, to measure the involvement of the glia and compare it with that of the neurons. The results obtained showed that BF powder contains polyphenols and flavonoids and that it is able to exercise an antioxidant property. Moreover, BF exerts a protective action on the damage induced by treatment with Aß, and this defense is found in experiments on the cell viability, on the accumulation of reactive oxygen species, on the involvement of the expression of caspase-3, and on necrotic or apoptotic death. In all these results, oligodendrocytes were always more sensitive and fragile than neurons. Further experiments are needed, and if this trend is confirmed, BF could be used in AD; at the same time, it could help to avoid the accumulation of waste products.

DEAD-Box Helicase 17 Promotes Amyloidogenesis by Regulating BACE1 Translation.

Amyloidogenesis is one of the key pathophysiological changes in Alzheimer's disease (AD). Accumulation of the toxic Aß results from the catalytic processing of ß-amyloid precursor protein (APP) associated ß-amyloid converting enzyme 1 (BACE1) activity. It is reported that dead-box helicase 17 (DDX17) controls RNA metabolism and is involved in the development of multiple diseases. However, whether DDX17 might play a role in amyloidogenesis has not been documented. In the present study, we found that DDX17 protein level was significantly increased in HEK and SH-SY5Y cells that stably express full-length APP (HEK-APP and Y5Y-APP) and in the brain of APP/PS1 mice, an animal model of AD. DDX17 knockdown, as opposed to DDX17 overexpression, markedly reduced the protein levels of BACE1 and the ß-amyloid peptide (Aß) in Y5Y-APP cells. We further found that DDX17-mediated enhancement of BACE1 was selectively attenuated by translation inhibitors. Specifically, DDX17 selectively interacted with the 5' untranslated region (5'UTR) of BACE1 mRNA, and deletion of the 5'UTR abolished the effect of DDX17 on luciferase activity or protein level of BACE1. Here, we show that the enhanced expression of DDX17 in AD was associated with amyloidogenesis; through the 5'UTR-dependent BACE1 translation, DDX17 might serve as an important mediator contributing to the progression of AD.

Small-molecule theranostics in Alzheimer's disease.

Alzheimer's Disease (AD) remains one of the most challenging health-related issues for our society. It is becoming increasingly prevalent, especially in developed countries, due to the rising life expectancy and, moreover, represents a considerable economic burden worldwide. All efforts at the discovery of new diagnostic and therapeutic tools in the last decades have invariably met with failure, making AD an incurable illness and underscoring the need for new approaches. In recent years, theranostic agents have emerged as an interesting strategy. They are molecules able to simultaneously provide diagnostic information and deliver therapeutic activity, allowing for the assessment of the molecule activity, the organism response and the pharmacokinetics. This makes these compounds promising for streamlining research on AD drugs and for their application in personalized medicine. We review here the field of small-molecule theranostic agents as promising tools for the development of novel diagnostic and therapeutic resources against AD, highlighting the positive and significant impact that theranostics can be expected to have in the near future in clinical practice.

Brain-targeted lycopene-loaded microemulsion modulates neuroinflammation, oxidative stress, apoptosis and synaptic plasticity in ß-amyloid-induced Alzheimer's disease mice.

OBJECTIVES: ß-Amyloid protein (Aß) plays pivotal roles in pathogenesis of Alzheimer's disease (AD) and triggers various pathophysiological events. Lycopene is a promising neuroprotector with multiple bioactivities, while its bioavailability is limited. Lycopene-loaded microemulsion (LME) possessing superior bioavailability and brain-targeting efficiency was developed in our previous study. In this investigation, we aimed to comprehensively evaluate its neuroprotective effects and underlying mechanisms using intracerebroventricular (ICV) Aß1-42 injection mice. METHODS: Mice were assigned to the Sham, Aß, Aß + LME and Aß + lycopene dissolved in olive oil (LOO) groups. ICV Aß1-42 administration was performed, followed by oral gavage of brain-targeted LME or conventional LOO formulation for 3 weeks. Brain samples were harvested for immunohistochemistry, biochemical assays and western blotting analyses. RESULTS: Our findings verified Aß-induced neurotoxicity on neuroinflammation, oxidative stress, apoptosis, Aß metabolisms and synaptic plasticity. LME supplementation dramatically attenuated astrocytosis and microgliosis, decreased malondialdehyde production and rescued antioxidant capacities, normalized apoptotic parameters and alleviated neuronal loss, inhibited amyloidogenic processing and activated non-amyloidogenic pathway, together with upregulating synaptic protein expressions and restoring synaptic plasticity. Nevertheless, most of these phenomena were not observed for mice treated with LOO, implying that LME showed significantly higher therapeutic efficacy against Aß injury. DISCUSSION: In summary, brain-targeted LME could exert neuroprotective function via suppressing a series of cascades triggered by Aß aggregates, thus ameliorating Aß neurotoxicity and associated abnormalities. Given this, LME may serve as an attractive candidate for AD prevention and treatment, and superiority of brain-targeting delivery is highlighted.

Protective effect of glutamic-oxaloacetic transaminase on hippocampal neurons in Alzheimer's disease using model mice.

Alzheimer's disease (AD), a neurodegenerative disease affecting the elderly, frequently causes cognitive impairment and memory decline, and there are currently no effective therapeutic drugs available. Glutamate excitotoxicity is one of the pathogeneses of AD, and there is evidence that glutamic-oxaloacetic transaminase (GOT) can significantly reduce glutamate concentrations in the hippocampi of mice, but its role in APP/PS1 transgenic mice is unknown. We investigated the improvement of neurological function and related protein expression following subcutaneous injection of GOT in mice with AD. We performed immunohistochemical staining on the brain tissue of 3-, 6-, and 12-month-old mice and found that the content of the ß-amyloid protein Aß1-42 in the 6 months old GOT treatment group was significantly reduced. Meanwhile, the APP-GOT group outperformed the APP group in the water maze and spatial object recognition experiments. The number of neurons in the hippocampal CA1 area of the APP-GOT group increased when compared to the APP group according to Nissl staining. Electron microscopic examination of the hippocampal CA1 area demonstrated that the number of synapses in the APP-GOT group was more than that in the APP group, and the mitochondrial structure was relatively complete. Finally, the protein content of the hippocampus was detected. In comparison to the APP group, SIRT1 content increased in the APP-GOT group whereas Aß1-42 content decreased, and Ex527 could reverse this trend. These results suggest that GOT can significantly improve the cognitive function of mice in the early stage of AD, and the underlying mechanism may be through decreasing Aß1-42 and increasing SIRT1 expressions.

Orexin-A aggravates cognitive deficits in 3xTg-AD mice by exacerbating synaptic plasticity impairment and affecting amyloid ß metabolism.

Dementia is the main clinical feature of Alzheimer's disease (AD). Orexin has recently been linked to AD pathogenesis, and exogenous orexin-A (OXA) aggravates spatial memory impairment in APP/PS1 mice. However, the effects of OXA on other types of cognitive deficits, especially in 3xTg-AD mice exhibiting both plaque and tangle pathologies, have not been reported. Furthermore, the potential electrophysiological mechanism by which OXA affects cognitive deficits and the molecular mechanism by which OXA increases amyloid ß (Aß) levels are unknown. In the present study, the effects of OXA on cognitive functions, synaptic plasticity, Aß levels, tau hyperphosphorylation, BACE1 and NEP expression, and circadian locomotor rhythm were evaluated. The results showed that OXA aggravated memory impairments and circadian rhythm disturbance, exacerbated hippocampal LTP depression, and increased Aß and tau pathologies in 3xTg-AD mice by affecting BACE1 and NEP expression. These results indicated that OXA aggravates cognitive deficits and hippocampal synaptic plasticity impairment in 3xTg-AD mice by increasing Aß production and decreasing Aß clearance through disruption of the circadian rhythm and sleep-wake cycle.

Epigallocatechin gallate-derived carbonized polymer dots: A multifunctional scavenger targeting Alzheimer's ß-amyloid plaques.

The design of high-efficiency scavengers targeting ß-amyloid protein (Aß) plaques in the progress of Alzheimer's disease (AD) has been recognized as an effective way to prevent and treat AD. Herein, epigallocatechin gallate (EGCG)-derived carbonized polymer dots (E-CPDs) were synthesized for the first time via a hydrothermal method using EGCG, an Aß inhibitor, as one of the raw materials. The inhibitory efficiency and fluorescent property of E-CPDs were elegantly modulated by adjusting the molar ratio of EGCG to nitrogen-containing dopant, o-phenylenediamine (oPD), and 75E-CPDs fabricated with 75 mM EGCG and 50 mM oPD showed the highest inhibitory capability. The multifunctionality of 75E-CPDs on inhibition of Aß fibrillization, Aß fibrils disaggregation, amyloid fluorescent detection, and intracellular reactive oxygen species scavenging was demonstrated. 75E-CPDs inhibited the formation of ß-sheet-rich Aß aggregates, alleviated Aß-induced cytotoxicity of cultured cells from 47% to 15%, and prolonged the lifespan of AD nematodes by scavenging in vivo amyloid plaques, demonstrating much higher performance than either EGCG or EGCG-free carbon dots. Notably, 75E-CPDs could rapidly disaggregate Aß fibrils on "second" scale, faster than any other disaggregating agents. The aromatic structure as well as hydroxyl and carboxyl groups existing on 75E-CPDs surface, which would interact with Aß species via hydrogen bonding, electrostatic interactions, and hydrophobic interactions, played critical roles in their inhibition and disaggregation capabilities. This work reveals that potent CDs can be fabricated by using an Aß inhibitor as the precursor, providing a new perspective for the design of multifunctional scavengers targeting amyloid plaques. STATEMENT OF SIGNIFICANCE: Alzheimer's disease (AD) is one of the top ten causes of death worldwide and seriously threatens human health. Recently, carbon nanomaterials have attracted much attention because of their good biocompatibility and capability in modulating Aß aggregation via multiple interactions. This work has for the first time fabricated epigallocatechin gallate-derived carbonized polymer dots (E-CPDs) and revealed the multifunctional potency of E-CPDs on alleviating the multifaced symptoms associated with ß-amyloid protein (Aß) fibrillization in the progression of AD. Notably, E-CPDs exhibited enhanced fluorescence emission upon binding to Aß fibrils, possessing potential as Aß fluorescent probes. It is believed that this work would open a new horizon in the design of multifunctional carbon nanomaterials as a potent amyloid scavenger for AD theranostics.

The role of LRP1 in Aß efflux transport across the blood-brain barrier and cognitive dysfunction in diabetes mellitus.

BACKGROUND: The incidence of cognitive dysfunction in diabetes is increasing yearly, which severely affects the quality of life of patients and places a heavy burden on families and society. It has been demonstrated that impaired clearance of cerebral amyloid ß-protein (Aß) is a central event in the initiation and progression of Aß deposition and cognitive impairment in diabetic patients. However, until now, the molecular mechanism by which diabetes mellitus induces impaired clearance of Aß has remained unclear. OBJECTIVE: To investigate the role and mechanism of lipoprotein receptor-related protein 1 (LRP1) in Aß clearance impairment and cognitive function damage caused by diabetes. METHODS: SPF male C57BL/6 mice were bred, and streptozotocin (STZ) (60 mg/kg/d) was intraperitoneally injected for 5 days to establish a diabetes model. The novel object recognition test and fear conditioning test were used to assess the cognitive function of mice in each group. Western blotting, qRT-PCR, ELISAs, and immunofluorescence staining were used to detect the expression levels of Aß and Aß clearance-related proteins in mouse brains. HBMECs were cultured in vitro to establish the blood-brain barrier model. The clearance rate of Aß and the expression levels of LRP1 were measured under different glucose concentration culture conditions. HBMECs were transfected with lentivirus to overexpress or knock down the LRP1, and then, the changes in Aß clearance were detected again. We injected adeno-associated virus AAV9-SP-A-LRP1 shRNA into the tail vein of DM mice to selectively knock down LRP1 gene expression in cerebral vascular endothelial cells. Then, the cognitive function and the expression levels of Aß and Aß clearance-related proteins in the brains of normal, DM and LRP1 knockdown mice were detected. RESULTS: Compared with the controls, diabetic mice showed impaired cognitive performance, increased deposition of Aß in the brain and decreased expression of LRP1 in the brain microvasculature. In vitro experiments showed that high glucose can downregulate the expression of LRP1 in HBMECs and damage the Aß clearance across the blood-brain barrier (BBB). The reduction in the clearance rate of Aß induced by high glucose was reversed by LRP1 overexpression but further substantially decreased when LRP1 was knocked down. CONCLUSION: Hyperglycemia can impair Aß efflux in the brain by downregulating the expression of LRP1 in the brain microvasculature, eventually resulting in cognitive impairment.

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.