Oxidative Stress In Alzheimer's Disease Research Articles

The Role of Reactive Oxygen Species in Alzheimer's Disease:from Mechanism to Biomaterials Therapy.

Alzheimer's disease (AD) is a chronic, insidious, and progressive neuro-degenerative disease that remains a clinical challenge for society. The fully approved drug lecanemab exhibits the prospect of therapy against the pathological processes, while debatable adverse events conflict with the drug concentration required for the anticipated therapeutic effects. Reactive oxygen species (ROS) are involved in the pathological progression of AD, as has been demonstrated in much research regarding oxidative stress (OS). The contradiction between anticipated dosage and adverse event may be resolved through targeted transport by biomaterials and get therapeutic effects through pathological progression via regulation of ROS. Besides, biomaterials fix delivery issues by promoting the penetration of drugs across the blood-brain barrier (BBB), protecting the drug from peripheral degradation, and elevating bioavailability. Our goal is to comprehensively understand the mechanisms of ROS in the progression of AD disease and the potential of ROS-related biomaterials in the treatment of AD. This review focuses on OS and its connection with AD and novel biomaterials in recent years against AD via OS to inspire novel biomaterial development. Revisiting these biomaterials and mechanisms associated with OS in AD via thorough investigations presents a considerable potential and bright future for improving effective interventions for AD. This article is protected by copyright. All rights reserved.

Oxidative Stress, Endoplasmic Reticulum Stress and Apoptosis in the Pathology of Alzheimer's Disease.

Alzheimer's disease (AD) accounts for a major statistic among the class of neurodegenerative diseases. A number of mechanisms have been identified in its pathogenesis and progression which include the amyloid beta (Aβ) aggregation, hyperphosphorylation of tau protein, oxidative stress, endoplasmic reticulum (ER) stress and apoptosis. These processes are interconnected and contribute significantly to the loss of neurons, brain mass and consequential memory loss and other cognitive difficulties. Oxidative stress in AD appears to be caused by excess of oxygen free radicals and extracellular Aβ deposits that cause local inflammatory processes and activate microglia, another possible source of reactive oxygen species (ROS). ER Stress describes the accumulation of misfolded and unfolded proteins as a result of physiological and pathological stimuli including high protein demand, toxins, inflammatory cytokines, and mutant protein expression that disturbs ER homeostasis. When compared to age-matched controls, postmortem brain tissues from AD patients showed elevated levels of ER stress markers, such as PERK, eIF2α, IRE1α, the chaperone Grp78, and the downstream mediator of cell death CHOP. Apoptosis is in charge of eliminating unnecessary and undesired cells to maintain good health. However, it has been demonstrated that a malfunctioning apoptotic pathway is a major factor in the development of certain neurological and immunological problems and diseases in people, including neurodegenerative diseases. This article highlights and discussed some of the experimentally established mechanisms through which these processes lead to the development as well as the exacerbation of AD.

Curculigoside, a traditional Chinese medicine monomer, ameliorates oxidative stress in Alzheimer's disease mouse model via suppressing ferroptosis.

Alzheimer's disease (AD) is a neurodegenerative disorder where oxidative stress, induced by ferroptosis, has been linked to neuronal damage and cognitive deficits. The objective of this study is to investigate if the potential therapeutic agent, Curculigoside (CUR), could ameliorate AD by inhibiting ferroptosis. The potential therapeutic targets, such as GPX4 and SLC7A11, were identified using weighted gene co-expression network analysis (WGCNA). Concurrently, CUR was also screened against these potential targets using various analytical methods. For the in vivo studies, intragastric administration of CUR significantly ameliorated cognitive impairment in AD model mice induced by scopolamine and okadaic acid (OA). In vitro, CUR protected neuronal cells by altering the levels of ferroptosis-related specific markers in OA and scopolamine-induced neurotoxicity. The administration of CUR through intragastric route significantly reduced the levels of AD-promoting factors (such as Aβ1-42 , p-tau) and ferroptosis-promoting factors in the hippocampus and cortex of AD mice. Furthermore, CUR up-regulated the expression of GPX4 and decreased the expression of SLC7A11 in the ferroptosis signaling pathway, thereby increasing the ratio of glutathione (GSH)/oxidized glutathione (GSSG) in vivo and vitro. In conclusion, the cumulative results suggest that the natural compound CUR may serve as a promising therapeutic agent to ameliorate AD by inhibiting ferroptosis.

NRF2 Deficiency Promotes Ferroptosis of Astrocytes Mediated by Oxidative Stress in Alzheimer's Disease.

Oxidative stress is involved in the pathogenesis of Alzheimer's disease (AD), which is linked to reactive oxygen species (ROS), lipid peroxidation, and neurotoxicity. Emerging evidence suggests a role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a major source of antioxidant response elements in AD. The molecular mechanism of oxidative stress and ferroptosis in astrocytes in AD is not yet fully understood. Here, we aimed to investigate the mechanism by which Nrf2 regulates the ferroptosis of astrocytes in AD. We found decreased expression of Nrf2 and upregulated expression of the ROS marker NADPH oxidase 4 (NOX4) in the frontal cortex from patients with AD and in the cortex of 3×Tg mice compared to wildtype mice. We demonstrated that Nrf2 deficiency led to ferroptosis-dependent oxidative stress-induced ROS with downregulated heme oxygenase-1 and glutathione peroxidase 4 and upregulated cystine glutamate expression. Moreover, Nrf2 deficiency increased lipid peroxidation, DNA oxidation, and mitochondrial fragmentation in mouse astrocytes (mAS, M1800-57). In conclusion, these results suggest that Nrf2 deficiency promotes ferroptosis of astrocytes involving oxidative stress in AD.

Oxidative stress in Alzheimer's disease: current knowledge of signaling pathways and therapeutics.

Alzheimer's disease's pathophysiology is still a conundrum. Growing number of evidences have elucidated the involvement of oxidative stress in the pathology of AD rendering it a major target for therapeutic development. Reactive oxygen species (ROS) generated by altered mitochondrial function, dysregulated electron transport chain and other sources elevate aggregated Aβ and neurofibrillary tangles which further stimulating the production of ROS. Oxidative stress induced damage to lipids, proteins and DNA result in neuronal death which leads to AD. In addition, oxidative stress induces apoptosis that is triggered by the modulation of ERK1/2 and Nrf2 pathway followed by increased GSK-3β expression and decreased PP2A activity. Oxidative stress exaggerates disease condition by interfering with various signaling pathways like RCAN1, CREB/ERK, Nrf2, PP2A, NFκB and PI3K/Akt. Studies have reported the role of TNF-α in oxidative stress stimulation that has been regulated by drugs like etanercept increasing the level of anti-oxidants. Other drugs like pramipexole, memantine, carvedilol, and melatonin have been reported to activate CREB/RCAN1 and Nrf2 pathways. In line with this, epigallocatechin gallate and genistein also target Nrf2 and CREB pathway leading to activation of downstream pathways like ARE and Keap1 which ameliorate oxidative stress condition. Donepezil and resveratrol reduce oxidative stress and activate AMPK pathway along with PP2A activation thus promoting tau dephosphorylation and neuronal survival. This study describes in detail the role of oxidative stress in AD, major signaling pathways involving oxidative stress induced AD and drugs under development targeting these pathways which may aid in therapeutic advances for AD.

Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer's disease models.

Introduction: Alzheimer's disease (AD) is a debilitating, progressive, neurodegenerative disorder characterized by the deposition of amyloid-β (Aβ) peptides and subsequent oxidative stress, resulting in a cascade of cytotoxic effects. Fangchinoline (Fan), a bisbenzylisoquinoline alkaloid isolated from traditional Chinese herb Stephania tetrandra S. Moorec, has been reported to possess multiple potent biological activities, including anti-inflammatory and antioxidant properties. However, the potential neuroprotective efficacy of Fan against AD remains unknown. Methods: N2AAPP cells, the mouse neuroblastoma N2A cells stably transfected with human Swedish mutant APP695, were served as an in vitro AD model. A mouse model of AD was constructed by microinjection of Aβ1-42 peptides into lateral ventricle of WT mice. The neuroprotective effects of Fan on AD were investigated through a combination of Western blot analysis, immunoprecipitation and behavioral assessments. Results and discussion: It was found that Fan effectively attenuated the amyloidogenic processing of APP by augmenting autophagy and subsequently fostering lysosomal degradation of BACE1 in N2AAPP cells, as reflected by the decrease in P62 levels, concomitant with the increase in Beclin-1 and LC3-II levels. More importantly, Fan significantly ameliorated cognitive impairment in an Aβ1-42-induced mouse model of AD via the induction of autophagy and the inhibition of oxidative stress, as evidenced by an increase in antioxidants including glutathione reductase (GR), total antioxidant capacity (T-AOC), nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and superoxide dismutase-1 (SOD-1) and a decrease in pro-oxidants including hydrogen peroxide (H2O2) and inducible nitric oxide synthase (i-NOS), coupled with a reduction in apoptosis marker, cleaved caspase-3. Taken together, our study demonstrate that Fan ameliorates cognitive dysfunction through promoting autophagy and mitigating oxidative stress, making it a potential therapeutic agent for AD.

Ameliorative effect of β‐pinene targeting mitochondrial dysfunction and oxidative stress in Alzheimer’s disease

AbstractBackgroundSporadic Alzheimer’s disease (sAD) is the most common type of dementia, characterized by the deposition of extracellular senile plaques, neurofibrillary tangles (NFTs), and neurodegeneration, leading to memory impairment and dementia. Intracerebroventricular (ICV) streptozotocin (STZ) mimics sporadic Alzheimer’s disease (sAD) characterized by neurodegeneration arising from oxidative stress, and mitochondrial dysfunction. β‐pinene is a monoterpene having antioxidant properties interlinked with mitochondrial functioning. To study the neuroprotective and cognitive enhancement properties of β‐pinene on mitochondrial dysfunction, oxidative stress, and histological changes in an animal model of Alzheimer’s disease induced by ICV‐STZ.MethodTo establish the sAD model, intracerebroventricular (ICV) streptozotocin (STZ) at a dose of 3 mg/kg was administered bilaterally in rats on a stereotaxic apparatus. Behavioral tests such as Morris water maze (MWM), novel object recognition (NOR) and Actophotometer were performed to evaluate spatial & recognition memory and locomotor functions. Three treatment doses (50mg/kg, 100 mg/kg and 200mg/kg) of Beta pinene (β‐pinene) and Galantamine (2 mg/kg) as a reference drug were given orally to ICV‐STZ induced rats for 21 days. Cortical and hippocampal tissues were dissected. Estimation of oxidative stress, mitochondrial dysfunction as complex I, II, III, IV activity and acetylcholinesterase activity were performed for cholinergic function. Moreover, histopathology was evaluated by hematoxylin and eosin (H&E) staining.Resultβ‐pinene treatment attenuated ICV‐STZ‐induced cognitive impairment in MWM and NOR. There is no significant effect revealed on locomotor activities. Moreover, in the cortex and hippocampal area of the brain, Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were normalized. Furthermore, reduced glutathione (GSH), catalase, superoxide dismutase (SOD), and (Lipid peroxidation) LPO were also reversed. β‐pinene prevents neurodegeneration as examined in histopathology.ConclusionIn the ICV‐STZ rat model, β‐pinene was found to be neuroprotective by reducing oxidative stress and mitochondrial dysfunction, consequently enhancing cognitive functions indicated in the behavioral outcomes.

Pengaruh Pemberian Mesenchymal Stem Cells Wharton’s Jelly terhadap Ekspresi Gen PPAR-γ pada Tikus Alzheimer

The increased production of beta-amyloid marks Alzheimer's disease. PPAR-γ shows involvement in Alzheimer's disease. PPAR-γ Gene is suspected to reduce beta-amyloid plaques and reduce inflammation and oxidative stress in Alzheimer's disease. Mesenchymal Stem Cells Wharton's Jelly (MSC-WJ) is expected to increase the PPAR-γ Gene expression. Objective:  To observed the PPAR-γ Gene expression in Alzheimer's Mice. Methods: The mice are induced using AlCl3 and were given MSC-WJ. This study was an experimental study with a post-test-only control group design on 18 samples of RNA from Alzheimer's mice that were divided into 3 groups. Negative control group (K-), positive control group (K+), and experimented group (P). The mean of PPAR-γ gene expression was obtained by comparing the PPAR-γ gene with the GAPDH gene. This study used semiquantitative methods using ImageJ. Data analysis was used with the Kruskal-Wallis test. It is significant if the value is <0,05. Results: The mean ratio of PPAR-γ gene expression that was obtained in K-, K+, and P were 0.12, 0.06, and 0.08, respectively. There were significant differences between each group, with a p-value of 0,023 (p<0,05). Conclusion: Giving MSC-WJ could increase the PPAR-γ gene expression. Further study using real-time PCR is highly needed to increase the MSC-WJ treatment in patients with Alzheimer's disease.Keywords:  Alzheimer disease, MSC-WJ, PPAR- γ

Targeting lncRNA NEAT1 hampers Alzheimer's disease progression.

Long noncoding RNA nuclear enriched abundant transcript 1 (lnc-NEAT1) is closely implicated in neurological diseases, while its implication in Alzheimer's disease (AD) is rarely reported. This study aimed to investigate the effect of lnc-NEAT1 knockdown on neuron injury, inflammation, and oxidative stress in AD, as well as its interaction with downstream targets and pathways. APPswe/PS1dE9 transgenic mice were injected with negative control or lnc-NEAT1 interference lentivirus. Besides, AD cellular model was constructed by amyloid β treatment in mice primary neuron cells; then, knockdown of lnc-NEAT1 and microRNA-193a was performed alone or in combination. In vivo experiments revealed that Lnc-NEAT1 knockdown improved cognition in AD mice reflected by Morrison water maze and Y-maze assays. Besides, lnc-NEAT1 knockdown reduced injury and apoptosis, decreased inflammatory cytokine levels, repressed oxidative stress level, and activated adenosine cyclophosphate response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) and nuclear factor erythroid 2-related factor 2 (NRF2)/nicotinamide adenine dinucleotide phosphate dehydrogenase 1 (NQO1) pathways in hippocampi of AD mice. Notably, lnc-NEAT1 down-regulated microRNA-193a both in vitro and in vivo and acted as a decoy of microRNA-193a. In vitro experiments showed that lnc-NEAT1 knockdown decreased apoptosis and oxidative stress, improved cell viability, also activated CREB/BDNF and NRF2/NQO1 pathways in AD cellular model. Meanwhile, microRNA-193a knockdown showed the opposite effects, which also attenuated lnc-NEAT1 knockdown-mediated reduction in injury, oxidative stress, and CREB/BDNF and NRF2/NQO1 pathways of AD cellular model. In conclusion, lnc-NEAT1 knockdown reduces neuron injury, inflammation, and oxidative stress through activating microRNA-193a mediated CREB/BDNF and NRF2/NQO1 pathways in AD.

Evaluation of the relationship among gene expressions and enzyme activities with antioxidant role and presenilin 1 expression in Alzheimer's disease.

It is known that oxidative stress originating from reactive oxygen species plays a role in the pathogenesis of Alzheimer's disease. In this study, the role of antioxidant status associated with oxidative stress in Alzheimer's disease was investigated. Peripheral blood samples were obtained from 28 healthy individuals (as control) and 28 Alzheimer's patients who met the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria. Catalase, glutathione S-transferase and paraoxonase 1 enzyme activities in blood plasma and glutathione S-transferase enzyme activities in erythrocytes were determined by spectrophotometer. Catalase, glutathione S-transferase and presenilin 1 gene expressions in leukocytes were determined using qRT-PCR. Data were analysed with SPSS one-way anova, a LSD post hoc test at p < 0.05. The activity of each enzyme was significantly reduced in Alzheimer's patients compared to control. The catalase gene expression level did not change compared to the control. Glutathione S-transferase and presenilin 1 gene expression levels were increased compared to the control.

A Triterpenoid Lupeol as an Antioxidant and Anti-Neuroinflammatory Agent: Impacts on Oxidative Stress in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease illustrated by neuronal dysfunctions, leading to memory weaknesses and personality changes mostly in the aged population worldwide. The exact cause of AD is unclear, but numerous studies have addressed the involvement of oxidative stress (OS), induced by reactive oxygen species (ROS), to be one of the leading causes in developing AD. OS dysregulates the cellular homeostasis, causing abnormal protein and lipid metabolism. Nutrition plays a pivotal role in modulating the antioxidant system and decreases the neuronal ROS level, thus playing an important therapeutic role in neurodegenerative diseases, especially in AD. Hence, medicinal herbs and their extracts have received global attention as a commercial source of antioxidants Lupeol. Lupeol is a pentacyclic triterpenoid and has many biological functions. It is available in fruits, vegetables, and medicinal plants. It has shown effective antioxidant and anti-inflammatory properties, and higher blood–brain barrier permeability. Also, the binding and inhibitory potentials of Lupeol have been investigated and proved to be effective against certain receptor proteins and enzymes in AD studies by computational molecular docking approaches. Therefore, AD-related research has gained interest in investigating the therapeutic effects of Lupeol. However, despite its beneficial effects in AD, there is still a lack of research in Lupeol. Hence, we compiled in this analysis all preclinical research that looked at Lupeol as an antioxidant and anti-inflammatory agent for AD.

Benzenesulfonamide as a novel, pharmaceutical small molecule inhibitor on Aβ gene expression and oxidative stress in Alzheimer's Wistar rats

Alzheimer's disease (AD) is the most prevalent acute neurodegenerative disease described by memory loss and other cognitive functions. Benzenesulfonamide, a novel, potent, and small organic molecule, was synthesized to investigate its effects on the levels of oxidative biomarkers (GPx, ROS, and MDA) and expression of beta-amyloid peptides (Aβ40 and Aβ42) in the pathology of AD. The results were compared with the rivastigmine drug. Applying benzenesulfonamide to Alzheimer's-induced Wistar rats showed a significant increase in the level of oxidative biomarkers (GPx, ROS, and MDA) in both the brain and blood serum as well as amyloid-β40 and 42 gene expressions. Therefore, benzenesulfonamide could be considered a novel therapeutic agent against AD.

Ferroptosis Signaling Pathways: Alzheimer's Disease.

The involvements of iron metabolism, lipid peroxidation, and oxidative stress in Alzheimer's disease (AD) development have recently received a lot of attention. We also observe that these pathogenic occurrences play a key role in regulating ferroptosis, a unique regulatory cell death that is iron-dependent, oxidative, and non-apoptotic. Iron is a crucial component that makes up a subunit of the oxidase responsible for lipid peroxidation. A family of non-heme iron enzymes known as lipoxygenases (LOXs) can cause ferroptosis by oxidising polyunsaturated fatty acids in cellular membranes (PUFAs). Toxic lipid hydroperoxides are produced in large part by the iron in LOX active sites. Deferoxamine and deferiprone, two iron chelators, could also treat ferroptosis by eliminating the crucial catalytic iron from LOXs. Phospholipids containing polyunsaturated fatty acids are the main substrates of lipid peroxidation in ferroptosis, which is favourably controlled by enzymes like ACSL4, LPCAT3, ALOXs, or POR. Selective stimulation of autophagic degradation pathways leads to an increase in iron accumulation and lipid peroxidation, which promotes ferroptosis. We highlighted recent advancements in our understanding of ferroptosis signaling routes in this study. One form of regulated necrotic cell death known as ferroptosis has been linked to a number of diseases, including cancer, neurological disorders, and ischemia/reperfusion injury. Cerebrospinal fluid (CSF) ferritin may be a good indicator of the amount of iron in the brain because it is the main protein that stores iron.

Dimethyl Fumarate as Potential Treatment for Alzheimer's Disease: Rationale and Clinical Trial Design.

Alzheimer's Disease (AD) is a debilitating disease that leads to severe cognitive impairment and functional decline. The role of tau hyperphosphorylation and amyloid plaque deposition in the pathophysiology of AD has been well described; however, neuroinflammation and oxidative stress related to sustained microglial activation is thought to play a significant role in the disease process as well. NRF-2 has been identified in modulating the effects of inflammation and oxidative stress in AD. Activation of NRF-2 leads to an increased production of antioxidant enzymes, including heme oxygenase, which has been shown to have protective effects in neurodegenerative disorders such as AD. Dimethyl fumarate and diroximel fumarate (DMF) have been approved for the use in relapsing-remitting multiple sclerosis. Research indicates that they can modulate the effects of neuroinflammation and oxidative stress through the NRF-2 pathway, and as such, could serve as a potential therapeutic option in AD. We propose a clinical trial design that could be used to assess DMF as a treatment option for AD.

Role of oxidative stress in Alzheimer's disease

Alzheimer's disease is the leading cause of disability in people over 65. Amyloid (Aβ) peptide deposition, neurofibrillary tangles of hyperphosphorylated protein, and dementia are hallmarks of AD [1]. The neurotoxic oligomer Aβ peptide and tau protein [2] mediate neurodegeneration, one of the main causes of the disease. Oxidative stress [3], an imbalance between antioxidants and oxidants, causes and exacerbates these symptoms. Free radicals, which have one or more unpaired electrons in their outer shell, can augment or reduce antioxidant defence, causing this imbalance. The reduction of molecular oxygen in water produces superoxide, which produces hydrogen peroxide by adding an electron. Reactive oxygen species (ROS) [4]—hydroxyl radicals produced by hydrogen peroxide reduction—can react with lipids, proteins, nucleic acids, and other molecules and change their structures and activities. Due to its makeup, ROS affects tissues and organs, particularly the sensitive brain. High oxygen usage and highly oxidizable lipids make up the brain.

Resveratrol-loaded selenium/chitosan nano-flowers alleviate glucolipid metabolism disorder-associated cognitive impairment in Alzheimer's disease

Resveratrol (Res) is a common natural polyphenol that inhibits inflammation and oxidative stress in Alzheimer's disease (AD). However, the absorption efficiency and in vivo bioactivity of Res are poor. High fat diet-induced metabolic disorders, including obesity and insulin resistance, can promote AD-related β-amyloid (Aβ) aggregation, Tau protein phosphorylation and neurotoxicity. Gut microbiota play a role in modulating metabolic syndrome and cognitive impairment. Herein, flower-like Res-loaded selenium nanoparticles/chitosan nanoparticles (Res@SeNPs@Res-CS-NPs) with higher loading capacity (64 %) were prepared to regulate gut microbiota in cases of AD with metabolic disorder. The nano-flowers could restore gut microbiota homeostasis to reduce lipopolysaccharide (LPS) formation and LPS-induced neuroinflammation. Additionally, Res@SeNPs@Res-CS-NPs can prevent lipid deposition and insulin resistance by decreasing Firmicutes levels and increasing Bacteroidetes levels in the gut, further inhibiting Aβ aggregation and Tau protein phosphorylation through the JNK/AKT/GSK3β signaling pathway. Moreover, Res@SeNPs@Res-CS-NPs treatment was able to regulate the relative levels of gut microbiota associated with oxidative stress, inflammation and lipid deposition, including Entercoccus, Colidextribacter, Rikenella, Ruminococcus, Candidatus_Saccharimonas, Alloprevotella and Lachnospiraceae_UCG-006. Overall, Res@SeNPs@Res-CS-NPs significantly enhances cognitive ability in AD mice with metabolic disorder, highlighting their potential for preventing cognitive impairments in AD.

Dietary Protection against Cognitive Impairment, Neuroinflammation and Oxidative Stress in Alzheimer’s Disease Animal Models of Lipopolysaccharide-Induced Inflammation

Alzheimer's disease (AD) is a rapidly growing epidemic with a heavy social and economic burden. Evidence suggests that systemic inflammation, dysregulation of the immune response and the resulting neuroinflammation and neurodegeneration play a significant role in AD pathogenesis. Currently, given that there is no fully convincing cure for AD, the interest in lifestyle factors (such as diet), which potentially delay onset and reduce the severity of symptoms, is increasing. This review is aimed at summarizing the effects of dietary supplementation on cognitive decline, neuroinflammation and oxidative stress in AD-like animal models with a focus on neuroinflammation induced by lipopolysaccharide (LPS) injection, which mimics systemic inflammation in animals. The compounds reviewed include curcumin, krill oil, chicoric acid, plasmalogens, lycopene, tryptophan-related dipeptides, hesperetin and selenium peptides. Despite the heterogeneity of these compounds, there is a strong consensus on their counteracting action on LPS-induced cognitive deficits and neuroinflammatory responses in rodents by modulating cell-signaling processes, such as the NF-κB pathway. Overall, dietary interventions could represent an important resource to oppose AD due to their influence in neuroprotection and immune regulation.

Caffeine improves memory and cognition via modulating neural progenitor cell survival and decreasing oxidative stress in Alzheimer's rat model.

Caffeine possesses potent antioxidant, anti-inflammatory and anti-apoptotic activities against a variety of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). The goal of this study was to investigate the protective role of a psychoactive substance like caffeine on hippocampal neurogenesis and memory functions in streptozotocin (STZ)-induced neurodegeneration in rats. Caffeine is a natural CNS stimulant, belonging to the methylxanthine class, and is a widely consumed psychoactive substance. It is reported to abate the risk of various abnormalities that are cardiovascular system (CVS) related, cancer related, or due to metabolism dysregulation. Short-term caffeine exposure has been widely evaluated, but its chronic exposure is less explored and pursued. Several studies suggest a devastating role of caffeine in neurodegenerative disorders. However, the protective role of caffeine on neurodegeneration is still unclear. Here, we examined the effects of chronic caffeine administration on hippocampal neurogenesis in intracerebroventricular STZ injection induced memory dysfunction in rats. The chronic effect of caffeine on proliferation and neuronal fate determination of hippocampal neurons was evaluated by co-labeling of neurons by thymidine analogue BrdU that labels new born cells, DCX (a marker for immature neurons) and NeuN that labels mature neurons. STZ (1 mg/kg, 2 μl) was injected stereotaxically into the lateral ventricles (intracerebroventricular injection) once on day 1, followed by chronic treatment with caffeine (10 mg/kg, i.p) and donepezil (5 mg/kg, i.p.). Protective effect of caffeine on cognitive impairment and adult hippocampal neurogenesis was evaluated. Our findings show decreased oxidative stress burden and amyloid burden following caffeine administration in STZ lesioned SD rats. Further, double immunolabeling with bromodeoxyuridine+/doublecortin+ (BrdU+/DCX+) and bromodeoxyuridine+/ neuronal nuclei+ (BrdU+/NeuN+) has indicated that caffeine improved neuronal stem cell proliferation and long term survival in STZ lesioned rats. Our findings support the neurogenic potential of caffeine in STZ induced neurodegeneration.

Advances in Antioxidant Nanomedicines for Imaging and Therapy of Alzheimer's Disease.

Significance: Reactive oxygen species (ROS) are crucial signaling molecules in the regulation of numerous physiological activities including the formation and function of the central nervous system (CNS). So far, many functional antioxidant nanomedicines with ROS scavenging capability to reduce oxidative stress in Alzheimer's disease (AD) have been developed for both imaging and therapy of AD. Recent Advances: This review focuses on the most recent advances in antioxidant nanomedicines such as ROS-scavenging nanoparticles (NPs), NPs with intrinsic antioxidant activity, and drug-loaded antioxidant NPs for AD theranostics. In addition to antioxidant nanomedicines, the emerging phototherapy treatment paradigms and the promising preclinic drug carriers, such as exosomes and liposomes, are also introduced. Critical Issues: In general, excessive generation of ROS can cause lipid peroxidation, oxidative DNA, as well as protein damage, aggravating pathogenic alterations, accumulation of amyloid-beta plaques and neurofibrillary tangles in the brain. These negative factors further cause cell death, which is the beginning of AD. Future Directions: We anticipate that this review will help researchers in the area of preclinical research and clinical translation of antioxidant nanomedicines for AD imaging and therapy.

Imine-Linked Covalent Organic Framework Modulates Oxidative Stress in Alzheimer’s Disease

Oxidative stress due to Cu2+-triggered aggregation of β-amyloid protein (Aβ) and reactive oxygen species (ROS) overexpression in the brain is an important hallmark of early stages of Alzheimer's disease (AD) pathogenesis. The ideal modulator for improving the oxidative stress microenvironment in AD brains should take both Cu2+ and ROS into consideration, which has been rarely reported. Here, a combined therapeutic strategy was achieved by co-encapsulating superoxide dismutase (SOD) and catalase (CAT) in imine-linked covalent organic frameworks (COFs), which were modified with peptide KLVFF (T5). The nanocomposite SC@COF-T5 exhibited an oxidative stress eradicating ability through ROS elimination and Cu2+ chelation, combined with the inhibition of Aβ42 monomer aggregation and disaggregation of Aβ42 fibrils. In vivo experiments indicated that SC@COF-T5 with a high blood-brain barrier (BBB) penetration efficiency was effective to reduce Aβ deposition, expression of pro-inflammatory cytokines, ROS levels, and neurologic damage in AD model mice, consequently rescuing memory deficits of AD mice. This work not only confirms the feasibility and merits of the therapeutic strategy regarding multiple targets for treatment of early AD pathogenesis but also opens up a novel direction for imine-linked COFs in biomedical applications.