The synergistic effect of curcumin and mitoquinol mesylate on cognitive impairment and the neuropathology of Alzheimer's disease.

Given the complexity and heterogeneity of Alzheimer's disease (AD) pathology, targeted monotherapy drugs may not be effective. Therefore, synergistic combination therapy of curcumin and Mito Q was proposed and evaluated in a triple-transgenic AD model mice (3 × Tg-AD mice). The cognitive ability was assessed using behavioral tests and typical pathological changes were observed through Western blotting and histological analysis. The results demonstrated a significant enhancement in cognitive ability along with the mitigation of typical AD pathological features such as Aß aggregation, tau phosphorylation, and synaptic damage. Notably, the combination therapy demonstrated superior efficacy over individual drugs alone. These findings provide valuable insights for optimizing the development of AD drugs.

Dissecting the chiral recognition of TLR4/MD2 with Neoseptin-3 enantiomers by molecular dynamics simulations.

Toll-like receptor 4 (TLR4) is a pivotal innate immune recognition receptor that regulates intricate signaling pathways within the immune system. Neoseptin-3 (Neo-3), a recently identified small-molecule agonist for mouse TLR4/MD2, exhibits chiral recognition properties. Specifically, the L-enantiomer of Neo-3 (L-Neo-3) effectively activates the TLR4 signaling pathway, while D-Neo-3 fails to induce TLR4 activation. However, the underlying mechanism by which TLR4 enantioselectively recognizes Neo-3 enantiomers remains poorly understood. In this study, in silico simulations were performed to investigate the mechanism of chiral recognition of Neo-3 enantiomers by TLR4/MD2. Two L-Neo-3 molecules stably resided within the cavity of MD2 as a dimer, and the L-Neo-3 binding stabilized the (TLR4/MD2)2 dimerization state. However, the strong electrostatic repulsion between the hydrogen atoms on the chiral carbon of D-Neo-3 molecules caused the relative positions of two D-Neo-3 molecules to continuously shift during the simulation process, thus preventing the formation of D-Neo-3 dimer as well as their stable interactions with the surrounding residues in (TLR4/MD2)2. Considering that L-Neo-3 could not sustain a stable dimeric state in the bulk aqueous environment, it is unlikely that L-Neo-3 entered the cavity of MD2 as a dimeric unit. Umbrella sampling simulations revealed that the second L-Neo-3 molecule entering the cavity of MD2 exhibited a lower binding energy (-25.75 kcal mol-1) than that of the first L-Neo-3 molecule (-14.31 kcal mol-1). These results imply that two L-Neo-3 molecules enter the cavity of MD2 sequentially, with the binding of the first L-Neo-3 molecule facilitating the entry of the second one. This study dissects the binding process of Neo-3 enantiomers, offering a comprehensive understanding of the atomic-level mechanism underlying TLR4's chiral recognition of Neo-3 molecules.

Se-methylselenocysteine ameliorates mitochondrial function by targeting both mitophagy and autophagy in the mouse model of Alzheimer's disease.

Background: Alzheimer's disease (AD) exerts tremendous pressure on families and society due to its unknown etiology and lack of effective treatment options. Our previous study had shown that Se-methylselenocysteine (SMC) improved the cognition and synaptic plasticity of triple-transgenic AD (3 × Tg-AD) mice and alleviated the related pathological indicators. We are dedicated to investigating the therapeutic effects and molecular mechanisms of SMC on mitochondrial function in 3 × Tg-AD mice. Methods: Transmission electron microscopy (TEM), western blotting (WB), mitochondrial membrane potential (ΔΨm), mitochondrial swelling test, and mitochondrial oxygen consumption test were used to evaluate the mitochondrial morphology and function. Mitophagy flux and autophagy flux were assessed with immunofluorescence, TEM and WB. The Morris water maze test was applied to detect the behavioral ability of mice. Results: The destroyed mitochondrial morphology and function were repaired by SMC through ameliorating mitochondrial energy metabolism, mitochondrial biogenesis and mitochondrial fusion/fission balance in 3 × Tg-AD mice. In addition, SMC ameliorated mitochondria by activating mitophagy flux via the BNIP3/NIX pathway and triggering autophagy flux by suppressing the Ras/Raf/MEK/ERK/mTOR pathway. SMC remarkably increased the cognitive ability of AD mice. Conclusions: This research indicated that SMC might exert its therapeutic effect by protecting mitochondria in 3 × Tg-AD mice.

The pharmacology and therapeutic role of cannabidiol in diabetes.

In recent years, cannabidiol (CBD), a non-psychotropic cannabinoid, has garnered substantial interest in drug development due to its broad pharmacological activity and multi-target effects. Diabetes is a chronic metabolic disease that can damage multiple organs in the body, leading to the development of complications such as abnormal kidney function, vision loss, neuropathy, and cardiovascular disease. CBD has demonstrated significant therapeutic potential in treating diabetes mellitus and its complications owing to its various pharmacological effects. This work summarizes the role of CBD in diabetes and its impact on complications such as cardiovascular dysfunction, nephropathy, retinopathy, and neuropathy. Strategies for discovering molecular targets for CBD in the treatment of diabetes and its complications are also proposed. Moreover, ways to optimize the structure of CBD based on known targets to generate new CBD analogues are explored.

Zinc exacerbates tau-induced Alzheimer-like pathology in C57BL/6J mice.

The pathogenesis of Alzheimer's disease (AD) is highly complex and multifactorial. Compared with Aß, the pathological changes associated with tau are more related to the clinical symptoms and more indicative of the severity of AD. Studies have shown that the direct interaction between tau and Zn2+ plays an important role in tau toxicity, however, the mechanism by which Zn2+ contributes to tau-induced neurotoxicity is not fully understood. Our previous studies have found that Zn2+ bound to the third repeat unit of the microtubule-binding domain of tau (R3) with moderate affinity and induced R3 to form oligomers, thus increased the toxicity of R3 to nerve cells. Here, we demonstrated that Zn2+ binding to R3 (Zn2++R3) significantly reduced cognitive ability and increased blood lipid and glucose levels of C57BL/6J mice. In addition, Zn2++R3, not Zn2+ or R3 alone, markedly enhanced the endogenous Aß and tau pathology and damaged the neurons of C57BL/6J mice. The study suggests that the main reason for the toxicity of Zn2+ may be the formation of Zn2+ and tau complex. Thus, preventing the combination of Zn2+ and tau may be a potential strategy for AD treatment. Furthermore, as the C57BL/6J mice injected with Zn2++R3 complex showed behavioral deficits, deposition of Aß plaques and tau tangles, and the death of neurons within 45 days. Thus, they can be considered as a fast sporadic AD or other tauopathies mouse model.

Dissecting the species-specific recognition of Neoseptin 3 by TLR4/MD2 via molecular dynamics simulations.

Toll-like receptor 4 (TLR4) is crucial in the innate immune response with species-specific recognition. As a novel small-molecule agonist for mouse TLR4/MD2, Neoseptin 3 fails to activate human TLR4/MD2, while the underlying mechanism is unclear. Herein, molecular dynamics simulations were performed to investigate the species-specific molecular recognition of Neoseptin 3. Lipid A, a classic TLR4 agonist showing no apparent species-specific sensing by TLR4/MD2, was also investigated for comparison. Neoseptin 3 and lipid A showed similar binding patterns with mouse TLR4/MD2. Although the binding free energies of Neoseptin 3 interacting with TLR4/MD2 from mouse and human species were similar, protein-ligand interactions and the details of the dimerization interface were substantially different between Neoseptin 3-bound mouse and human heterotetramers at the atomic level. Neoseptin 3 binding made human (TLR4/MD2)2 more flexible than human (TLR4/MD2/Lipid A)2, especially at the TLR4 C-terminus and MD2, which drives human (TLR4/MD2)2 fluctuating away from the active conformation. In contrast to mouse (TLR4/MD2/2*Neoseptin 3)2 and mouse/human (TLR4/MD2/Lipid A)2 systems, Neoseptin 3 binding to human TLR4/MD2 led to the separating trend of the C-terminus of TLR4. Furthermore, the protein-protein interactions at the dimerization interface between TLR4 and the neighboring MD2 in the human (TLR4/MD2/2*Neoseptin 3)2 system were much weaker than those of the lipid A-bound human TLR4/MD2 heterotetramer. These results explained the inability of Neoseptin 3 to activate human TLR4 signaling and accounted for the species-specific activation of TLR4/MD2, which provides insight for transforming Neoseptin 3 as a human TLR4 agonist.

In vivo visualization of enantioselective targeting of amyloid and improvement of cognitive function by clickable chiral metallohelices.

The pathogenesis of Alzheimer's disease (AD) is closely related to several contributing factors, especially amyloid-ß (Aß) aggregation. Bioorthogonal reactions provide a general, facile, and robust route for the localization and derivatization of Aß-targeted agents. Herein, a pair of chiral alkyne-containing metallohelices (ΛA and ΔA) were demonstrated to enantioselectively target and modulate Aß aggregation, which has been monitored in triple-transgenic AD model mice and proved to improve cognitive function. Compared with its enantiomer ΔA, ΛA performed better in blocking Aß fibrillation, relieving Aß-triggered toxicity, and recovering memory deficits in vivo. Moreover, clickable ΛA could act as a functional module for subsequent visualization and versatile modification of amyloid via bioorthogonal reaction. As a proof-of-concept, thioflavin T, tacrine, and magnetic nanoparticles were conjugated with ΛA to realize Aß photo-oxygenation, acetylcholinesterase inhibition, and Aß clearance, respectively. This proof-of-principle work provided new insights into the biolabeling and bioconjugation of multifunctional metallosupramolecules through click reactions for AD therapy.

The protective effects of Esculentoside A through AMPK in the triple transgenic mouse model of Alzheimer's disease.

BACKGROUND: Neurofibrillary tangles comprising hyperphosphorylated tau are vital factors associated with the pathogenesis of Alzheimer's disease (AD). The elimination or reduction of hyperphosphorylated and abnormally aggregated tau is a valuable measure in AD therapy. Esculentoside A (EsA), isolated from Phytolacca esculenta, exhibits pharmacotherapeutic efficacy in mice with amyloid beta-induced AD. However, whether EsA affects tau pathology and its specific mechanism of action in AD mice remains unclear. PURPOSE: To investigate the roles and mechanisms of EsA in cognitive decline and tau pathology in a triple transgenic AD (3 × Tg-AD) mouse model. METHODS: EsA (5 and 10 mg/kg) was administered via intraperitoneal injection to 8-month-old AD mice for eight consecutive weeks. Y-maze and novel object recognition tasks were used to evaluate the cognitive abilities of mice. Potential signaling pathways and targets in EsA-treated AD mice were assessed using quantitative proteomic analysis. The NFT levels and hippocampal synapse numbers were investigated using Gallyas-Braak silver staining and transmission electron microscopy, respectively. Western blotting and immunofluorescence assays were used to measure the expression of tau-associated proteins. RESULTS: EsA administration attenuated memory and recognition deficits and synaptic damage in AD mice. Isobaric tags for relative and absolute quantitation proteomic analysis of the mouse hippocampus revealed that EsA modulated the expression of some critical proteins, including brain-specific angiogenesis inhibitor 3, galectin-1, and Ras-related protein 24, whose biological roles are relevant to synaptic function and autophagy. Further research revealed that EsA upregulated AKT/GSK3ß activity, in turn, inhibited tau hyperphosphorylation and promoted autophagy to clear abnormally phosphorylated tau. In hippocampus-derived primary neurons, inhibiting AMP-activated protein kinase (AMPK) activity through dorsomorphin could eliminate the effect of EsA, as revealed by increased tau hyperphosphorylation, downregulated activity AKT/GSK3ß, and blocked autophagy. CONCLUSIONS: To our knowledge, this study is the first to demonstrate that EsA attenuates cognitive decline by targeting the pathways of both tau hyperphosphorylation and autophagic clearance in an AMPK-dependent manner and it shows a high reference value in AD pharmacotherapy research.

Ebselen Interferes with Alzheimer's Disease by Regulating Mitochondrial Function.

(1) Background: With unknown causes and no effective treatment available, Alzheimer's disease (AD) places enormous pressure on families and society. Our previous study had shown that Ebselen at a high concentration (10.94 µM) improved the cognition of triple-transgenic AD (3×Tg-AD) mice and alleviated the related pathological indicators but showed toxicity to the mice. Here, we dedicated to study the therapeutic effect and molecular mechanism of Ebselen at a much lower concentration on 3×Tg-AD mice. (2) Methods: Various behavioral experiments were applied to detect the behavioral ability of mice. Western blot, thioflavin T staining and a transmission electron microscope were used to evaluate the pathology of AD mice. The mitochondrial membrane potential and respiration were assessed with the corresponding assay kit. (3) Results: Ebselen remarkably increased cognitive ability of AD mice, eliminated ß-Amyloid (Aß) oligomers and recovered the synaptic damage in AD mice brain. In addition, the destroyed mitochondrial morphologies and function were repaired by Ebselen through ameliorating mitochondrial energy metabolism, mitochondrial biogenesis and mitochondrial fusion/fission balance in N2a-SW cells and brain tissues of AD mice. (4) Conclusions: This research indicated that Ebselen might exert its therapeutic effect via protecting mitochondria in AD.

DHA Ameliorates Cognitive Ability, Reduces Amyloid Deposition, and Nerve Fiber Production in Alzheimer's Disease.

Background: The etiology of Alzheimer's disease (AD) is very complex. Docosahexaenoic acid (DHA) is important in cognitive ability and nervous system development. A limited number of studies have evaluated the efficacy of DHA in the treatment of AD. Introduction: We detected neurofibrillary tangles (NFT) in the hippocampus and cortex of transgenic mice brain through silver glycine staining. We determined the activity of neurons by staining Nissl bodies, used liquid NMR to detect metabolites in the brain, and functional magnetic resonance imaging results to observe the connection signal value between brain regions. Materials and Methods: We fed 3-month-old APP/PS1 double transgenic mice with DHA mixed feeds for 4 months to assess the effects of DHA on cognitive ability in AD mice through the Morris water maze and open field tests. To evaluate its effects with AD pathology, continuous feeding was done until the mice reached 9 months of age. Results: Compared to AD mice, escape latency significantly decreased on the fifth day while swimming speed, target quadrant stay time, and the crossing number of platforms increased by varying degrees after DHA treatment. Brain tissue section staining revealed that DHA significantly reduced Aß and nerve fibers in the brain of AD mice. Conclusion: DHA significantly reduced the deposition of Aß in the brain and inhibited the production of nerve fibers, thereby increasing cognitive abilities in AD mice. In addition, DHA suppressed blood lipid levels, and restored uric acid and urea levels, implying that DHA is a potential therapeutic option for early AD.

Hydrogen-Bonded Organic Framework (HOF)-Based Single-Neural Stem Cell Encapsulation and Transplantation to Remodel Impaired Neural Networks.

Herein we present a new way to encapsulate neural stem cells (NSCs) by using hydrogen-bonded organic frameworks (HOFs) to overcome the common causes of low therapeutic efficacy during NSC transplantation: 1) loss of fundamental stem cell properties, "stemness", before transplantation, 2) cytomembrane damage during transplantation, and 3) apoptosis due to oxidative stress after transplantation. Porous carbon nanospheres (PCNs) are doped into the HOF shell during the process of mineralization to endow the cellular exoskeletons with hierarchical hydrogen bonds, and the ability to resist oxidative stress due to the catalase and superoxide dismutase-like activities of PCN. Under NIR-II irradiation, thermal-responsive hydrogen bonds dissociate to release NSCs. Stereotactic transplanting encapsulated NSC into the brain of an Alzheimer's disease (AD) mouse model further verifies that our design can enhance NSC viability, promote neurogenesis, and ameliorate cognitive impairment. As the first example of using HOFs to encapsulate NSCs, this work may inspire the design of HOF-based exoskeletons to ameliorate neurogenesis and cognitive behavioral symptoms associated with AD.

Esculentoside A alleviates cognitive deficits and amyloid pathology through peroxisome proliferator-activated receptor γ-dependent mechanism in an Alzheimer's disease model.

BACKGROUND: Alzheimer's disease (AD) is characterized clinically by cognitive deficits and pathologically by amyloid-ß (Aß) deposition and tau aggregation, as well as the brain atrophy. Esculentoside A (EsA), a neuroprotective saponin, is isolated from Phytolacca esculenta and shows potent health-promoting effects in a variety of experimental models. However, there are minimal reports on the effects of EsA on triple transgenic AD mice. PURPOSE: The current research aimed at investigating the protective effects and underlying mechanisms of EsA on the mitigation of cognitive deficits and pathology in triple transgenic AD mice. METHODS: Triple transgenic AD mice (3 × Tg-AD) of 8 months old received intraperitoneal treatment of 5 or 10 mg/kg EsA for 8 consecutive weeks. Morris water maze test and open field test were made to evaluate the cognitive function and degree of anxiety of the mice. Liquid chromatography with tandem mass spectrometry analysis was performed to characterize and to quantify EsA in the blood and brain of mice. Immunofluorescence assay and Western blot were adopted to measure the levels of peroxisome proliferator-activated receptor gamma (PPARγ) and key proteins in Aß pathology, ER stress- and apoptosis-associated pathways. The combination of EsA with PPARγ were theoretically calculated by molecular docking programs and experimentally confirmed by the bio-layer interferometry technology. RESULTS: Supplemental EsA could improve the cognitive deficits of 3 × Tg-AD mice. EsA penetrated the brain-blood barrier to exert a strong effect on AD mice, evidenced as decreasing Aß generation, reducing the degrees of oxidative and ER stress, and mitigating neuronal apoptosis through the increase of PPARγ expression. In the culture of primary neurons, addition of PPARγ inhibitor GW9662 eliminated the effects of EsA on AD pathologies. Direct combination of EsA with PPARγ were demonstrated by molecular docking programs and bio-layer interferometry technology. CONCLUSIONS: For the first time, these outcomes revealed that EsA could penetrate the brain-blood barrier to exert a strong effect on ameliorating cognitive deficits in 3 × Tg-AD mice and exert neuroprotective effects toward AD pathology via PPARγ-dependent mechanism.

Hydrogen-rich water ameliorates neuropathological impairments in a mouse model of Alzheimer's disease through reducing neuroinflammation and modulating intestinal microbiota.

Hydrogen exhibits the potential to treat Alzheimer's disease. Stereotactic injection has been previously used as an invasive method of administering active hydrogen, but this method has limitations in clinical practice. In this study, triple transgenic (3×Tg) Alzheimer's disease mice were treated with hydrogen-rich water for 7 months. The results showed that hydrogen-rich water prevented synaptic loss and neuronal death, inhibited senile plaques, and reduced hyperphosphorylated tau and neurofibrillary tangles in 3×Tg Alzheimer's disease mice. In addition, hydrogen-rich water improved brain energy metabolism disorders and intestinal flora imbalances and reduced inflammatory reactions. These findings suggest that hydrogen-rich water is an effective hydrogen donor that can treat Alzheimer's disease. This study was approved by the Animal Ethics and Welfare Committee of Shenzhen University, China (approval No. AEWC-20140615-002) on June 15, 2014.

Near-infrared target enhanced peripheral clearance of amyloid-ß in Alzheimer's disease model.

Clearance of peripheral amyloid-ß (Aß) has been demonstrated particularly promising for overcoming the blood-brain barrier (BBB) hurdle to remove brain-derived Aß associated with Alzheimer's disease (AD). However, currently used therapeutic agents targeting peripheral Aß cannot simultaneously achieve plasma Aß enrichment and enhanced clearance, which may result in poor bioavailability and rather low efficacy. Moreover, most of therapeutic agents usually promote the unfavorable aggregation of Aß. Herein, we construct a near-infrared (NIR) regulated surface-transformable and target peptide-guided upconversion platform (UCNP/ONA-P/K), serving as a safe and effective way for Aß clearance. Taking advantage of extended blood circulation, high selectivity toward Aß, and surface-transformable property, such UCNP/ONA-P/K can address the challenges of peripheral Aß clearance by a combination of enhancing the enrichment of plasma Aß, preventing the unfavorable aggregation of Aß and simultaneously facilitating the hepatic clearance of the captured Aß. After verified by a series of systematic toxicity evaluation, cell uptake, deep tissue penetration, and hemolytic experiments, in vivo studies demonstrate that UCNP/ONA-P/K can efficiently decrease brain Aß burden and reverse memory deficits in 3xTg-AD mice. Overall, this NIR multi-functional design provides a new biocompatible and efficient way for Aß removal, which will promote the application of peripheral clearance of Aß for AD treatment.

Bis(ethylmaltolato)oxidovanadium (IV) alleviates neuronal apoptosis through regulating peroxisome proliferator-activated receptor γ in a triple transgenic animal model of Alzheimer's disease.

Endoplasmic reticulum stress (ER stress) plays a critical role in neuronal apoptosis along with the aggravation of Alzheimer's disease (AD). Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that is involved in regulating ER stress in Alzheimer's disease (AD), therefore, this protein could be a promising therapeutic target for AD. Vanadium compounds, such as vanadyl acetylacetonate, sodium metavanadate and bis(maltolato)oxovanadium, are well-known as puissant PPARγ modulators. Thus, we are curious whether bis(ethylmaltolato)oxidovanadium (IV) (BEOV) can ameliorate ER stress and subsequent neuronal apoptosis by regulating PPARγ in AD models. To this end, we determined the effect of BEOV on behavioral performance, ER stress and neuronal apoptosis in the triple transgenic mouse AD model (3×Tg-AD). Our results showed that BEOV improved cognitive abilities and reduced the ER stress- and apoptosis-associated proteins in the brains of 3×Tg-AD mice. In vitro administration of BEOV in primary hippocampal neurons and N2asw cells achieved similar results in repressing ER stress. In addition, cotreatment with GW9662 (an antagonist of PPARγ) effectively blocked these neuroprotective effects of BEOV, which provided strong evidence that PPARγ-dependent signaling plays a key role in protecting against ER stress and neuronal apoptosis in AD. In conclusion, our data demonstrated that BEOV alleviated neuronal apoptosis triggered by ER stress by regulating PPARγ in a 3×Tg-AD model.

Isobavachalcone ameliorates cognitive deficits, and Aß and tau pathologies in triple-transgenic mice with Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects 50 million people worldwide. The current medicines have modest benefits in preventing or curing AD. Thus, it is urgent to discover drugs with the potential to change the progression of the disease. The primary clinical symptoms are memory loss and anxiety, while the critical pathological characteristics are Aß plaques and hyperphosphorylated tau tangles. In this study, isobavachalcone (ISO), isolated from Psoralea corylifolia, was administered to 3×Tg-AD mice. It has been shown that this compound could significantly improve anxiety, memory and recognition deficits in the AD mice, attenuate the accumulation of Aß oligomers, reduce the hyperphosphorylation of tau, and prevent the production of tau filaments. The metabolomic analysis implicates that the most probable pathways affected by ISO were bile secretion, tyrosine metabolism, and purine metabolism. In summary, ISO possesses the potential for further development as a drug candidate for AD.

Bis(ethylmaltolato)oxidovanadium (IV) attenuates amyloid-beta-mediated neuroinflammation by inhibiting NF-κB signaling pathway via a PPARγ-dependent mechanism.

Neuroinflammation plays a pivotal role in the pathophysiology of neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. During brain neuroinflammation, activated microglial cells resulting from amyloid-beta (Aß) overload trigger toxic proinflammatory responses. Bis(ethylmaltolato)oxidovanadium (BEOV) (IV), an important vanadium compound, has been reported to have anti-diabetic, anti-cancer, and neuroprotective effects, but its anti-inflammatory property has rarely been investigated. In the present study, the inhibitory effects of BEOV on neuroinflammation were revealed in both Aß-stimulated BV2 microglial cell line and APPswe/PS1E9 transgenic mouse brain. BEOV administration significantly decreased the levels of tumor necrosis factor-α, interleukin-6, interleukin-1ß, inducible nitric oxide synthase, and cyclooxygenase-2 both in the hippocampus of APPswe/PS1E9 mice and in the Aß-stimulated BV2 microglia. Furthermore, BEOV suppressed the Aß-induced activation of nuclear factor-κB (NF-κB) signaling and upregulated the protein expression level of peroxisome proliferator-activated receptor gamma (PPARγ) in a dose-dependent manner. PPARγ inhibitor GW9662 could eliminate the effect of BEOV on Aß-induced NF-κB activation and proinflammatory mediator production. Taken altogether, these findings suggested that BEOV ameliorates Aß-stimulated neuroinflammation by inhibiting NF-κB signaling pathway through a PPARγ-dependent mechanism.

Se-Methylselenocysteine (SMC) Improves Cognitive Deficits by Attenuating Synaptic and Metabolic Abnormalities in Alzheimer's Mice Model: A Proteomic Study.

Se-methylselenocysteine (SMC) is a major selenocompound in selenium (Se) enriched plants and has been found to ameliorate neuropathology and cognitive deficits in triple-transgenic mice model of Alzheimer's disease (3 × Tg-AD mice). To explore the underlying molecular mechanisms, the present study is designed to elucidate the protein changes in the cortex of SMC-treated 3 × Tg-AD mice. After SMC supplementation, proteomic analysis revealed that 181, 271, and 41 proteins were identified as differentially expressed proteins (DEPs) between 3 × Tg-AD mice vs wild type (AD/WT group), SMC-treated AD mice vs AD (AD + SMC/AD), and AD + SMC/WT group, respectively. Among these, 138 proteins in the diseased group were reversed by SMC treatment. The DEPs in AD/WT group and AD + SMC/AD group were mainly related to metabolism, synapses, and antioxidant proteins, while their levels were decreased in AD mice but up-regulated after treating with SMC. In addition, we found reduced ATP levels and destroyed synaptic structures in the AD mice brains, which were significantly ameliorated upon SMC treatment. Our study suggests that energy metabolism disorders, abnormal amino acid metabolism, synaptic dysfunction, and oxidative stress may be the key pathogenic phenomena of AD. SMC reversed the expression of proteins associated with them, which might be the main mechanism of its intervention in AD.

Unsaturated mannuronate oligosaccharide ameliorates ß-amyloid pathology through autophagy in Alzheimer's disease cell models.

Unsaturated mannuronate oligosaccharide (MOS) is an enzymatic depolymerization product from alginate-derived polymannuronate (PM). In this study, we investigated for the first time the potential therapeutic effect of MOS on Alzheimer's disease (AD) and its molecular mechanism in N2a-sw cells and 3×Tg-AD primary cortex neurons. Our results showed that MOS ranges from mannuronate dimer to mannuronate undecamer (M2-M11) with an unsaturated nonreducing terminal structure and with a double bond and 1,4-glycosidic linkages. It significantly inhibited the aggregation of amyloid-ß (Aß)1-42 oligomer, decreased expression of Aß1-42 and reduced levels of amyloid precursor protein (APP) and BACE1. It promoted the autophagy, which involves the inactivation of mTOR signaling pathway and the facilitation of the fusion of autophagosomes and lysosomes. Finally, autophagy inhibitors blocked MOS' anti-AD actions, confirming the involvement of autophagy. In conclusion, MOS from seaweed alginate might be a promising nutraceutical or natural medicine for AD therapy.

Self-Protecting Biomimetic Nanozyme for Selective and Synergistic Clearance of Peripheral Amyloid-ß in an Alzheimer's Disease Model.

Clearance of peripheral amyloid-ß (Aß) has been demonstrated to be promising for overcoming the blood-brain barrier (BBB) hurdle to eliminate brain-derived Aß associated with Alzheimer's disease (AD). Even so, current developed therapeutic assays for clearance of peripheral Aß are still facing challenges on how to avoid interference of certain biological molecules and prevent triggering the activation of immune responses and blood clotting. Here, a biomimetic nanozyme (CuxO@EM-K) with augmented protein adsorption resistance, minimized immunogenicity, and enhanced biocompatibility is designed and synthesized. The CuxO@EM-K is made of CuxO nanozyme wrapped with modified 3xTg-AD mouse erythrocyte membrane with Aß-targeting pentapeptide KLVFF. KLVFF serves as Aß-specific ligand that works together with erythrocyte membrane to selectively capture Aß in the blood. Meanwhile, the erythrocyte membrane coating prevents protein coronas formation and thus retains Aß-targeting ability of CuxO@EM-K in biological fluids. More importantly, the CuxO core with multiple antioxidant enzyme-like activities stabilizes the outer erythrocyte membrane and simultaneously mitigates Aß-induced membrane oxidative damage, which enables the extended systemic circulation indispensable for adsorbing Aß. In vivo studies demonstrate that CuxO@EM-K not only reduces Aß burden in the blood and brain but also ameliorates memory deficits in the widely used 3xTg-AD mouse model. Moreover, CuxO@EM-K shows no apparent toxicity in 3xTg-AD mice. Overall, this work provides an example for developing biocompatible and synergistic clearance of peripheral Aß associated with AD.