Synaptic adhesion molecule protocadherin-γC5 mediates ß-amyloid-induced neuronal hyperactivity and cognitive deficits in Alzheimer's disease.

Neuronal hyperactivity induced by ß-amyloid (Aß) is an early pathological feature in Alzheimer's disease (AD) and contributes to cognitive decline in AD progression. However, the underlying mechanisms are still unclear. Here, we revealed that Aß increased the expression level of synaptic adhesion molecule protocadherin-γC5 (Pcdh-γC5) in a Ca2+-dependent manner, associated with aberrant elevation of synapses in both Aß-treated neurons in vitro and the cortex of APP/PS1 mice in vivo. By using Pcdhgc5 gene knockout mice, we demonstrated the critical function of Pcdh-γC5 in regulating neuronal synapse formation, synaptic transmission, and cognition. To further investigate the role of Pcdh-γC5 in AD pathogenesis, the aberrantly enhanced expression of Pcdh-γC5 in the brain of APP/PS1 mice was knocked down by shRNA. Downregulation of Pcdh-γC5 efficiently rescued neuronal hyperactivity and impaired cognition in APP/PS1 mice. Our findings revealed the pathophysiological role of Pcdh-γC5 in mediating Aß-induced neuronal hyperactivity and cognitive deficits in AD and identified a novel mechanism underlying AD pathogenesis.

Diabetes mellitus and Alzheimer's disease: Vacuolar adenosine triphosphatase as a potential link.

Globally, the incidence of diabetes mellitus (DM) and Alzheimer's disease (AD) is increasing year by year, causing a huge economic and social burden, and their pathogenesis and aetiology have been proven to have a certain correlation. In recent years, more and more studies have shown that vacuolar adenosine triphosphatases (v-ATPases) in eukaryotes, which are biomolecules regulating lysosomal acidification and glycolipid metabolism, play a key role in DM and AD. This article describes the role of v-ATPase in DM and AD, including its role in glycolysis, insulin secretion and insulin resistance (IR), as well as its relationship with lysosomal acidification, autophagy and ß-amyloid (Aß). In DM, v-ATPase is involved in the regulation of glucose metabolism and IR. v-ATPase is closely related to glycolysis. On the one hand, v-ATPase affects the rate of glycolysis by affecting the secretion of insulin and changing the activities of key glycolytic enzymes hexokinase (HK) and phosphofructokinase 1 (PFK-1). On the other hand, glucose is the main regulator of this enzyme, and the assembly and activity of v-ATPase depend on glucose, and glucose depletion will lead to its decomposition and inactivation. In addition, v-ATPase can also regulate free fatty acids, thereby improving IR. In AD, v-ATPase can not only improve the abnormal brain energy metabolism by affecting lysosomal acidification and autophagy but also change the deposition of Aß by affecting the production and degradation of Aß. Therefore, v-ATPase may be the bridge between DM and AD.

Engineering Core/Ligands Interfacial Anchors of Nanoparticles for Efficiently Inhibiting Both Aß and Amylin Fibrillization.

Accurate construction of artificial nano-chaperones' structure is crucial for precise regulation of protein conformational transformation, facilitating effective treatment of proteopathy. However, how the ligand-anchors of nano-chaperones affect the spatial conformational changes in proteins remains unclear, limiting the development of efficient nano-chaperones. In this study, three types of gold nanoparticles (AuNPs) with different core/ligands interface anchor structures (Au─NH─R, Au─S─R, and Au─C≡C─R, R = benzoic acid) are synthesized as an ideal model to investigate the effect of interfacial anchors on Aß and amylin fibrillization. Computational results revealed that the distinct interfacial anchors imparted diverse distributions of electrostatic potential on the nanointerface and core/ligands bond strength of AuNPs, leading to differential interactions with amyloid peptides. Experimental results demonstrated that all three types of AuNPs exhibit site-specific inhibitory effects on Aß40 fibrillization due to preferential binding. For amylin, amino-anchored AuNPs demonstrate strong adsorption to multiple sites on amylin and effectively inhibit fibrillization. Conversely, thiol- and alkyne-anchored AuNPs adsorb at the head region of amylin, promoting folding and fibrillization. This study not only provided molecular insights into how core/ligands interfacial anchors of nanomaterials induce spatial conformational changes in amyloid peptides but also offered guidance for precisely engineering artificial-chaperones' nanointerfaces to regulate the conformational transformation of proteins.

Dual-Carbon Dots Composite: A Multifunctional Photo-Propelled Nanomotor Against Alzheimer's ß-Amyloid.

The abnormal accumulation of ß-amyloid protein (Aß) is considered as the main pathological hallmark of Alzheimer's disease (AD). The design of potent multifunctional theranostic agents targeting Aß is one of the effective strategies for AD prevention and treatment. Nanomotors as intelligent, advanced, and multifunctional nanoplatforms can perform many complex tasks, but their application in AD theranostics is rare. Herein, sub-10nm multifunctional dual-carbon dots composites (ERCD) with photo-propelled nanomotor behavior are fabricated by conjugating near-infrared (NIR) carbon dots (RCD) of thermogenic and photodynamic capability with the previously reported epigallocatechin gallate-derived carbonized polymer dots (ECD). ERCD-1 (ECD:RCD = 1:2.5) showed potent inhibitory capability similar to ECD in the absence of NIR light, and exhibited photooxygenation activity and nanomotor behavior powered by "self-thermophoretic force" under NIR irradiation, significantly enhancing the inhibition, disaggregation, and photooxygenation capabilities. The nanomotor suppressed Aß fibrillization and rapidly disaggregated mature Aß fibrils at very low concentrations (0.5 µg mL-1). Moreover, the NIR-activated ERCD-1 imaged Aß plaques in vivo and prolonged nematode lifespan by 6 d at 2 µg mL-1. As a proof-of-concept, this work opened a new avenue to the design of multifunctional sub-10nm nanomotors targeting Aß for AD theranostics.

Differential Synaptic Loss in ß-Amyloid Positive Versus ß-Amyloid Negative Corticobasal Syndrome.

BACKGROUND/OBJECTIVE: The corticobasal syndrome (CBS) is a complex asymmetric movement disorder, with cognitive impairment. Although commonly associated with the primary 4-repeat-tauopathy of corticobasal degeneration, clinicopathological correlation is poor, and a significant proportion is due to Alzheimer's disease (AD). Synaptic loss is a pathological feature of many clinical and preclinical tauopathies. We therefore measured the degree of synaptic loss in patients with CBS and tested whether synaptic loss differed according to ß-amyloid status. METHODS: Twenty-five people with CBS, and 32 age-/sex-/education-matched healthy controls participated. Regional synaptic density was estimated by [11C]UCB-J non-displaceable binding potential (BPND), AD-tau pathology by [18F]AV-1451 BPND, and gray matter volume by T1-weighted magnetic resonance imaging. Participants with CBS had ß-amyloid imaging with 11C-labeled Pittsburgh Compound-B ([11C]PiB) positron emission tomography. Symptom severity was assessed with the progressive supranuclear palsy-rating-scale, the cortical basal ganglia functional scale, and the revised Addenbrooke's Cognitive Examination. Regional differences in BPND and gray matter volume between groups were assessed by ANOVA. RESULTS: Compared to controls, patients with CBS had higher [18F]AV-1451 uptake, gray matter volume loss, and reduced synaptic density. Synaptic loss was more severe and widespread in the ß-amyloid negative group. Asymmetry of synaptic loss was in line with the clinically most affected side. DISCUSSION: Distinct patterns of [11C]UCB-J and [18F]AV-1451 binding and gray matter volume loss, indicate differences in the pathogenic mechanisms of CBS according to whether it is associated with the presence of Alzheimer's disease or not. This highlights the potential for different therapeutic strategies in CBSs. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Design, synthesis, and activity evaluation of novel multitargeted l-tryptophan derivatives with powerful antioxidant activity against Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurological disease, and the multitarget directed ligand (MTDL) strategy may be an effective approach to delay its progression. Based on this strategy, 27 derivatives of l-tryptophan, 3a-1-3d-1, were designed, synthesized, and evaluated for their biological activity. Among them, IC50 (inhibitor concentration resulting in 50% inhibitory activity) values of compounds 3a-18 and 3b-1 were 0.58 and 0.44 µM for human serum butyrylcholinesterase (hBuChE), respectively, and both of them exhibited more than 30-fold selectivity for human serum acetylcholinesterase. Enzyme kinetics studies showed that these two compounds were mixed inhibitors of hBuChE. In addition, these two derivatives possessed extraordinary antioxidant activity in OH radical scavenging and oxygen radical absorption capacity fluorescein assays. Meanwhile, these compounds could also prevent ß-amyloid (Aß) self-aggregation and possessed low toxicity on PC12 and AML12 cells. Molecular modeling studies revealed that these two compounds could interact with the choline binding site, acetyl binding site, and peripheral anionic site to exert submicromolar BuChE inhibitory activity. In the vitro blood-brain barrier permeation assay, compounds 3a-18 and 3b-1 showed enough blood-brain barrier permeability. In drug-likeness prediction, compounds 3a-18 and 3b-1 showed good gastrointestinal absorption and a low risk of human ether-a-go-go-related gene toxicity. Therefore, compounds 3a-18 and 3b-1 are potential multitarget anti-AD lead compounds, which could work as powerful antioxidants with submicromolar selective inhibitory activity for hBuChE as well as prevent Aß self-aggregation.

BHBA treatment improves cognitive function by targeting pleiotropic mechanisms in transgenic mouse model of Alzheimer's disease.

Accumulation of amyloid ß (Aß) peptide, inflammation, and oxidative stress contribute to Alzheimer's disease (AD) and trigger complex pathogenesis. The ketone body ß-hydroxybutyrate (BHBA) is an endogenous metabolic intermediate that protects against stroke and neurodegenerative diseases, but the underlying mechanisms are unclear. The present study aims to elucidate the protective effects of BHBA in the early stage of AD model and investigate the underlying molecular mechanisms. Three-and-half-month-old double-transgenic mice (5XFAD) overexpressing ß-amyloid precursor protein (APP) and presenilin-1 (PS1) were used as the AD model. The 5XFAD mice received 1.5 mmol/kg/d BHBA subcutaneously for 28 days. Morris water maze test, nest construction, and passive avoidance experiments were performed to assess the therapeutic effects on AD prevention in vivo, and brain pathology of 5XFAD mice including amyloid plaque deposition and microglia activation were assessed. Gene expression profiles in the cortexes of 5XFAD- and BHBA-treated 5XFAD mice were performed with high-throughput sequencing and bioinformatic analysis. Mouse HT22 cells were treated with 2 mM BHBA to explore its in vitro protective effects of BHBA on hippocampal neurons against Aß oligomer toxicity, ATP production, ROS generation, and mitochondrial aerobic respiratory function. APP, BACE1, and neprilysin (NEP) expression levels were evaluated in HT22 cells following treatment with BHBA by measuring the presence or absence of G protein-coupled receptor 109A (GPR109A). BHBA improved cognitive function of 5XFAD mice in Morris water maze test, nesting construction and passive avoidance experiments, and attenuated Aß accumulation and microglia overactivation in the brain. BHBA also enhanced mitochondrial respiratory function of hippocampal neurons and protected it from Aß toxicity. The enzymes, APP and NEP were regulated by BHBA via G-protein-coupled receptor 109A (GPR109A). Furthermore, RNA sequencing revealed that BHBA-regulated genes mainly annotated in aging, immune system, nervous system, and neurodegenerative diseases. Our data suggested that BHBA confers protection against the AD-like pathological events in the AD mouse model by targeting multiple aspects of AD and it may become a promising candidate for the prevention and treatment of AD.

RAGE induces physiological activation of NADPH oxidase in neurons and astrocytes and neuroprotection.

The transmembrane receptor for advanced glycation end products (RAGE) is a signaling receptor for many damage- and pathogen-associated molecules. Activation of RAGE is associated with inflammation and an increase in reactive oxygen species (ROS) production. Although several sources of ROS have been previously suggested, how RAGE induces ROS production is still unclear, considering the multiple targets of pathogen-associated molecules. Here, using acute brain slices and primary co-culture of cortical neurons and astrocytes, we investigated the effects of a range of synthetic peptides corresponding to the fragments of the RAGE V-domain on redox signaling. We found that the synthetic fragment (60-76) of the RAGE V-domain induces activation of ROS production in astrocytes and neurons from the primary co-culture and acute brain slices. This effect occurred through activation of RAGE and could be blocked by a RAGE inhibitor. Activation of RAGE by the synthetic fragment stimulates ROS production in NADPH oxidase (NOX). This RAGE-induced NOX activation produced only minor decreases in glutathione levels and increased the rate of lipid peroxidation, although it also reduced basal and ß-amyloid induced cell death in neurons and astrocytes. Thus, specific activation of RAGE induces redox signaling through NOX, which can be a part of a cell protective mechanism.

A Biomimetic Upconversion Nanobait-Based Near Infrared Light Guided Photodynamic Therapy Alleviates Alzheimer's Disease by Inhibiting ß-Amyloid Aggregation.

Aberrant ß-amyloid (Aß) fibrillation is the key event in Alzheimer's disease (AD), the inhibition and degradation of which are recognized as a promising therapeutic strategy to alleviate the nerve damage of AD. Photodynamic therapy (PDT) holds great potential for modulation of Aß self-assembly, which is nevertheless limited by the inefficient utilization of reactive oxygen species (ROS). Herein, an erythrocyte membrane (EM)-modified core-shell upconversion nanoparticle (UCNP/Cur@EM) is designed and fabricated as a biomimetic nanobait to improve the PDT efficiency in AD. The UCNP with the outlayer of mesoporous silica is synthesized to load a high amount of the photosensitizer (curcumin), the unique optical feature of which can trigger curcumin to generate ROS upon near-infrared light (NIR) irradiation. Integration of EM enables the biomimetic nanobait to attract Aß peptides trapped in the phospholipid bilayer, restraining the growth of Aß monomers to form aggregates and improving the utilization rate of ROS to degrade the preformed Aß aggregates. In vivo studies demonstrate that UCNP/Cur@EM irradiated by NIR enables to decrease Aß deposits, ameliorates memory deficits, and rescues cognitive functions in the APP/PS1 transgenic mouse model. A biocompatible and controllable way is provided here to inhibit the amyloid protein-associated pathological process of AD.

Co-Assembled Nanoparticles toward Multi-Target Combinational Therapy of Alzheimer's Disease by Making Full Use of Molecular Recognition and Self-Assembly.

The complex pathologies in Alzheimer's disease (AD) severely limit the effectiveness of single-target pharmic interventions, thus necessitating multi-pronged therapeutic strategies. While flexibility is essentially demanded in constructing such multi-target systems, for achieving optimal synergies and also accommodating the inherent heterogeneity within AD. Utilizing the dynamic reversibility of supramolecular strategy for conferring sufficient tunability in component substitution and proportion adjustment, amphiphilic calixarenes are poised to be a privileged molecular tool for facilely achieving function integration. Herein, taking ß-amyloid (Aß) fibrillation and oxidative stress as model combination pattern, a supramolecular multifunctional integration is proposed by co-assembling guanidinium-modified calixarene with ascorbyl palmitate and loading dipotassium phytate within calixarene cavity. Serial pivotal events can be simultaneously addressed by this versatile system, including 1) inhibition of Aß production and aggregation, 2) disintegration of Aß fibrils, 3) acceleration of Aß metabolic clearance, and 4) regulation of oxidative stress, which is verified to significantly ameliorate the cognitive impairment of 5×FAD mice, with reduced Aß plaque content, neuroinflammation, and neuronal apoptosis. Confronted with the extremely intricate clinical realities of AD, the strategy presented here exhibits ample adaptability for necessary alterations on combinations, thereby may immensely expedite the advancement of AD combinational therapy through providing an exceptionally convenient platform.

Long-Term High-Fat Diet Consumption Aggravates ß-Amyloid Deposition and Tau Pathology Accompanied by Microglial Activation in an Alzheimer's Disease Model.

Alzheimer's disease (AD) is the most prevailing form of dementia, with long-term high-fat diet (HFD) consumption being a pivotal contributor to AD pathogenesis. As microglial dysfunction is a crucial factor in the AD onset, it becomes imperative to explore the effects of HFD on microglial function and AD pathogenesis. In the present study, 3xTg-AD model mice at the age of 9-month are subjected to random allocation, with one group receiving a standard diet (ND) and the other an HFD for 3 months. Subsequently, transcriptomic profiling of microglia unveils that HFD alters fatty acid metabolism and mediates T cell infiltration. Within the hippocampus, microglia exhibit aberrant morphology and lipid accretion in response to the HFD, evidenced by conspicuously enlarged microglial cell bodies and accumulation of lipid droplets. These lipid-droplet-accumulating microglia exhibit diminished migratory capacity and compromise plaque consolidation, thereby exacerbating the accumulation of ß-amyloid. Noteworthy, the HFD induces T cell infiltration, thereby aggravating neuroinflammation and Tau phosphorylation. Morris water maze test reveals that HFD-consuming mice display marked impairment in memory performance. In summary, this study demonstrates that prolonged HFD consumption exacerbates amyloid deposition, tau pathology, and cognitive deficits, which is associated with the accumulation of lipid droplets within microglia.

Out-of-Equilibrium Mechanical Disruption of ß-Amyloid-Like Fibers using Light-Driven Molecular Motors.

Artificial molecular motors have the potential to generate mechanical work on their environment by producing autonomous unidirectional motions when supplied with a source of energy. However, the harnessing of this mechanical work to subsequently activate various endoenergetic processes that can be useful in materials science remains elusive. Here, it is shown that by integrating a light-driven rotary motor through hydrogen bonds in a ß-amyloid-like structure forming supramolecular hydrogels, the mechanical work generated during the constant rotation of the molecular machine under UV irradiation is sufficient to disrupt the ß-amyloid fibers and to trigger a gel-to-sol transition at macroscopic scale. This melting of the gel under UV irradiation occurs 25 °C below the temperature needed to melt it by solely using thermal activation. In the dark, a reversible sol-gel transition is observed as the system fully recovers its original microstructure, thus illustrating the possible access to new kinds of motorized materials that can be controlled by advanced out-of-equilibrium thermodynamics.

Innate neuroimmunity across aging and neurodegeneration: a perspective from amyloidogenic evolvability.

In Alzheimer's Disease (AD), amyloidogenic proteins (APs), such as ß-amyloid (Aß) and tau, may act as alarmins/damage-associated molecular patterns (DAMPs) to stimulate neuroinflammation and cell death. Indeed, recent evidence suggests that brain-specific type 2 immune networks may be important in modulating amyloidogenicity and brain homeostasis. Central to this, components of innate neuroimmune signaling, particularly type 2 components, assume distinctly specialized roles in regulating immune homeostasis and brain function. Whereas balanced immune surveillance stems from normal type 2 brain immune function, appropriate microglial clearance of aggregated misfolded proteins and neurotrophic and synaptotrophic signaling, aberrant pro-inflammatory activity triggered by alarmins might disrupt this normal immune homeostasis with reduced microglial amyloid clearance, synaptic loss, and ultimately neurodegeneration. Furthermore, since increased inflammation may in turn cause neurodegeneration, it is predicted that AP aggregation and neuroinflammation could synergistically promote even more damage. The reasons for maintaining such adverse biological conditions which have not been weeded out during evolution remain unclear. Here, we discuss these issues from a viewpoint of amyloidogenic evolvability, namely, aEVO, a hypothetic view of an adaptation to environmental stress by AP aggregates. Speculatively, the interaction of AP aggregation and neuroinflammation for aEVO in reproduction, which is evolutionally beneficial, might become a co-activating relationship which promotes AD pathogenesis through antagonistic pleiotropy. If validated, simultaneously suppressing both AP aggregation and specific innate neuroinflammation could greatly increase therapeutic efficacy in AD. Overall, combining a better understanding of innate neuroimmunity in aging and disease with the aEVO hypothesis may help uncover novel mechanism of pathogenesis of AD, leading to improved diagnostics and treatments.

[Corrigendum] Neuroprotective effect of emodin against Alzheimer's disease via Nrf2 signaling in U251 cells and APP/PS1 mice.

Subsequently to the publication of this paper, an interested reader drew to the authors' attention that the lower left panel of Fig. 3A of this paper had already featured in the following paper, which featured one of the same authors (Zhiping Li): Zhang Y, Wang J, Wang C, Li Z, Liu X, Zhang J, Lu J and Wang D: Pharmacological basis for the use of evodiamine in Alzheimer's disease: antioxidation and antiapoptosis. Int J Mol Sci 21: 1527, 2018. Moreover, an independent analysis of the data in this paper conducted by the Editorial Office revealed that the Bcl­2 protein western blotting data featured in Fig. 3C had apparently also appeared in a previous publication featuring the same author [Qiu Y, Jiang X, Liu D, Deng Z, Hu W, Li Z and Li Y: The hypoglycemic and renal protection properties of crocin via oxidative stress­regulated NF­κB signaling in db/db mice. Front Pharmacol 30: 541, 2020].  After having examined their original data, the authors have realized that Fig. 3 in the above paper had been inadvertently assembled incorrectly, owing to the mishandling of certain of the data. In addition, the authors wished to present a revised version of Fig. 4 containing more representative data for Fig. 4C and D. The corrected versions of Figs. 3 and 4, featuring the correct data for Fig. 3A and C, and the revised data in Fig. 4C and D, are shown on the next two pages. Note that these errors did not significantly affect the results or the conclusions reported in this paper, and all the authors agree to the publication of this Corrigendum. The authors are grateful to the Editor of Molecular Medicine Reports for granting them the opportunity to publish this corrigendum, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 23: 108, 2021; DOI: 10.3892/mmr.2020.11747].

Targeted brain delivery of RVG29-modified rifampicin-loaded nanoparticles for Alzheimer's disease treatment and diagnosis.

Alzheimer's disease (AD) is an aging-related neurodegenerative disease. The main pathological features of AD are ß-amyloid protein (Aß) deposition and tau protein hyperphosphorylation. Currently, there are no effective drugs for the etiological treatment of AD. Rifampicin (RIF) is a semi-synthetic broad-spectrum antibiotic with anti-ß-amyloid deposition, anti-inflammatory, anti-apoptosis, and neuroprotective effects, but its application in AD treatment has been limited for its strong hydrophobicity, high toxicity, short half-life, low bioavailability, and blood-brain barrier hindrance. We designed a novel brain-targeted and MRI-characteristic nanomedicine via loading rabies virus protein 29 (RVG29), rifampicin, and Gd on poly (l-lactide) nanoparticles (RIF@PLA-PEG-Gd/Mal-RVG29). The cytotoxicity assay demonstrated that RIF@PLA-PEG-Gd/Mal-RVG29 had favorable biocompatibility and security. Fluorescence imaging in vivo showed that PLA-PEG-Gd/Mal-RVG29 could deliver rifampicin into the brain by enhancing cellular uptake and brain targeting performance, leading to improvement of the bioavailability of rifampicin. In in vivo study, RIF@PLA-PEG-Gd/Mal-RVG29 improved the spatial learning and memory capability of APP/PS1 mice in the Morris water maze, as compared to rifampicin. Immunofluorescence, TEM, immunoblotting, and H&E staining revealed that RIF@PLA-PEG-Gd/Mal-RVG29 reduced Aß deposition in hippocampal and cortex of APP/PS1 mice, improved the damage of synaptic ultrastructure, increased the expression level of PSD95 and SYP, as well as reduced the necrosis of neurons. These findings suggest that RIF@PLA-PEG-Gd/Mal-RVG29 may be an effective strategy for the treatment of AD.

Neuroprotective effect of emodin against Alzheimer's disease via Nrf2 signaling in U251 cells and APP/PS1 mice.

Emodin is a naturally­occurring medicinal herbal ingredient that possesses numerous pharmacological properties, including anti­inflammatory and antioxidant effects. In the present study, potential neuroprotective effects associated with the antioxidant activity of emodin were assessed in U251 cells that were subjected to ß­amyloid peptide (Aß)­induced apoptosis and in amyloid precursor protein (APP)/presenilin­1 (PS1) double­transgenic mice. U251 is a type of human astroglioma cell line (cat. no. BNCC337874; BeNa Culture Collection). In apoptotic U251 cells, 3­h emodin pre­treatment prior to 24­h Aß co­exposure improved cell viability, suppressed lactate dehydrogenase leakage and caspase­3, ­8 and ­9 activation to inhibit apoptosis. Compared with those after Aß exposure alone, emodin ameliorated the dissipation of the mitochondrial membrane potential, inhibited the over­accumulation of reactive oxygen species, enhanced the expression levels of nuclear factor­erythroid­2­related factor 2 (Nrf2), haemeoxygenase­1, superoxide dismutase 1, Bcl­2 and catalase in addition to decreasing the expression levels of Bax. In APP/PS1 mice, an 8­week course of emodin administration improved spatial memory and learning ability and decreased anxiety. Emodin was also found to regulate key components in the Nrf2 pathway and decreased the deposition of Aß, phosphorylated­τ and 4­hydroxy­2­nonenal in APP/PS1 mice. Taken together, the present data suggest that emodin may serve as a promising candidate for the treatment of Alzheimer's disease.

CART mitigates oxidative stress and DNA damage in memory deficits of APP/PS1 mice via upregulating ß­amyloid metabolism­associated enzymes.

Alzheimer's disease (AD) is the most common form of dementia that is primarily characterized by progressive cognitive deficits. The toxicity of amyloid ß­protein (Aß) serves an important role in the progression of AD, resulting in neuronal loss via a number of possible mechanisms, including oxidative stress, mitochondrial dysfunction, energy depletion, apoptosis and neuroinflammation. Previous studies have reported that cocaine amphetamine regulated transcript (CART) treatment improves memory and synaptic structure in APP/PS1 mice. Therefore, the present study aimed to investigate whether CART served a protective role against memory deficits in AD. APP/PS1 mice were treated with CART or PBS. Spatial memory was assessed using the Morris water maze. Oxidative stress and DNA damage were compared among wild­type, APP/PS1 and CART­treated APP/PS1 mice. The mRNA and protein expression levels of Aß metabolism­associated enzymes, including neprilysin (NEP), insulin­degrading enzyme (IDE), receptor for advanced glycation end products (RAGE) and low­density lipoprotein receptor­related protein 1 (LRP­1), in the hippocampus were measured via reverse transcription­quantitative PCR and western blotting, respectively. CART improved the memory impairment of APP/PS1 mice by reducing oxidative stress, inhibiting DNA damage and protecting against mitochondrial dysfunction in the cerebral cortex and hippocampus. CART also reduced cell senescence and oxidative stress in Aß1­42­exposed primary cortical neurons in APP/PS1 mice. Moreover, CART promoted Aß degradation via modulating Aß metabolism­associated enzymes, including IDE, NEP, LRP­1 and RAGE. Collectively, the present study indicated that CART improved the learning and memory capacity of APP/PS mice, thus may have potential to serve as a novel therapeutic agent for AD.

Nogo­66 promotes ß­amyloid protein secretion via NgR/ROCK­dependent BACE1 activation.

The generation of ß­amyloid protein (Aß) is considered a key step in the pathogenesis of Alzheimer's disease (AD) and the regulation of its production is an important therapeutic strategy. It was hypothesized in the present study that Nogo­A may be involved in AD and may regulate the generation of Aß. Nogo­A is known to act as a major inhibitor of neuron regeneration in the adult central nervous system. A recent study indicated that Nogo­A is associated with AD; however, the underlying effect and molecular mechanisms remain largely elusive. In the present study, the potential effects of Nogo­A on AD were investigated. ELISA was used to detect the levels of Aß, enzymatic activity detection kits were used to determine the activity of secretase enzymes in amyloid precursor protein (APP) metabolism, and western blot analysis was used to detect the expression levels of proteins associated with the APP processing and Nogo­A/Nogo­66 receptor (NgR) signaling pathways. The results revealed that Nogo­66, the major inhibitory region of Nogo­A, promoted neuronal Aß secretion by increasing the activity of ß­secretase 1 via the NgR/Rho­associated coiled­coil containing kinases pathway in a dose­dependent manner. The present data suggested that Nogo­A may facilitate the onset and development of AD by promoting Aß secretion, providing information on a potential novel target for AD therapy.

[Effect of moxibustion on expression of RAGE and LRP-1 and neuronal ultrastructure of frontal cortex and hippocampus in vascular dementia rats].

OBJECTIVE: To explore the effect of moxibustion of acupoints of Governor Vessel on learning-memory ability and expression of the receptor for advanced glycation end products (RAGE), low density lipoprotein (LDL) receptor related protein-1 (LRP-1), ß-amyloid precursor protein (APP) and neuronal ultrastructure of the frontal cortex and hippocampus in vascular dementia (VD) rats, so as to investigate its underlying mechanisms in relieving VD. METHODS: A total of 24 male SD rats were randomized into normal, model, and moxibustion groups (n＝8 rats in each group). The VD model was established by occlusion of the bilateral common carotid arteries for 20 min and reperfusion for 10 min which was repeated for 3 times. Moxibustion was applied to "Baihui" (GV20), "Dazhui"(GV14) and "Fengfu"(GV16)for 30 min, once daily for 4 weeks. The learning-memory ability was evaluated by using Morris water maze tests. At the end of experiments, the frontal lobe of cerebral cortex and hippocampus tissues were collected for detecting the expression of RAGE and LRP-1 proteins with Western blot, and RAGE, LRP-1 and APP mRNAs with quantitative real-time PCR, respectively. The ultrastructure of neurons in the frontal cortex and hippocampal CA1 region was observed with transmission electron microscopy. RESULTS: Following modeling, Morris water maze tests showed that the average escape latency of the model group and moxibustion group was significantly prolonged on the 4th day of modeling (P<0.01). The expression levels of RAGE protein and mRNA and APP mRNA were significantly increased (P<0.01), while those of LRP-1 protein and mRNA in the cortex and hippocampus remarkably decreased in the model group relevant to the normal group (P<0.01). Following moxibustion, modeling-induced increase of expression of RAGE protein and mRNA and APP mRNA, and down-regulation of expression of LRP-1 protein and mRNA were reversed in the moxibustion group relevant to the model group (P<0.01). Results of electron microscopy showed dilation of the mitochondria with disappearance of the cristae, partial vacuolar degeneration or dissolved external membrane, and cytoplasmic edema with basic disappearance of the rough endoplasmic reticulum and glycogen particles in neurons of the frontal cortex and hippocampal CA1 region after modeling, which was relatively milder in the moxibustion group. CONCLUSION: Moxibustion of acupoints of the Governor Vessel may reduce the content of APP in the frontal cortex and hippocampus by regulating the expression of RAGE and LRP-1 proteins and mRNA in VD rats.

The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer's disease.

The beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) initiates the generation of amyloid-ß (Aß), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti-Aß therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE-1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Aß in rats and dogs, and Aß plaque deposition in APP-transgenic mice. Animal toxicology studies of CNP520 demonstrated sufficient safety margins, with no signs of hair depigmentation, retina degeneration, liver toxicity, or cardiovascular effects. In healthy adults ≥ 60 years old, treatment with CNP520 was safe and well tolerated and resulted in robust and dose-dependent Aß reduction in the cerebrospinal fluid. Thus, long-term, pivotal studies with CNP520 have been initiated in the Generation Program.