Aβ-induced Alzheimer's Disease Research Articles

The protective effect and bioactive compounds of Astragalus membranaceus against neurodegenerative disorders via alleviating oxidative stress in Drosophila.

Oxidative stress is proposed as a regulatory element in various neurological disorders, which is involved in the progress of several neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Antioxidant drugs are widely used to alleviate neurodegenerative disorders. Astragalus membranaceus (Huangqi, AM) is a commonly used medicinal herb with a wide range of pharmacological effects. Here, the protective effect and mechanism of AM extract (AME) and its bioactive compounds against neurodegenerative disorders via alleviating oxidative stress were detected using adult Drosophila melanogaster. The drug safety was measured by development analysis; oxidative stress resistance ability was detected by survival rate under H2O2 environment; ROS level was detected by DHE staining and gstD1-GFP fluoresence assay; antioxidative abilitiy was represent by measuring antioxidant enzyme activity, antioxidative-related gene expression, and ATP and MFN2 levels. The neuroprotective effect was evaluated by lifespan and locomotion analysis in Aβ42 transgenic and Pink1B9 mutants. AME dramatically increased the survival rates, improved the CAT activity, restored the decreased mRNA expressions of Sod1, Cat, and CncC under H2O2 stimulation, and ameliorated the neurobehavioral defects of the AD and PD. Thirteen small molecules in AM had antioxidant function, in which vanillic acid and daidzein had the most potent antioxidant effect. Vanillic acid and daidzein could increase the activities of SOD and CAT, GSH level, and the expressions of antioxidant genes. Vanillic acid could improve the levels of ATP and MFN2, and mRNA expressions of ND42 and SDHC to rescue mitochondrial dysfunction. Furthermore, vanillic acid ameliorated neurobehavioral defects of PD. Daidzein ameliorated neurobehavioral defect of Aβ-induced AD mode. Taken together, AM plays a protective role in oxidative damage, thereby as a potential natural drug to treat neurodegenerative disorders.

DEAD Box Helicase 24 Is Increased in the Brain in Alzheimer's Disease and AppN-LF Mice and Influences Presymptomatic Pathology.

At the time of diagnosis, Alzheimer's disease (AD) patients already suffer from significant neuronal loss. The identification of proteins that influence disease progression before the onset of symptoms is thus an essential part of the development of new effective drugs and biomarkers. Here, we used an unbiased 18O labelling proteomics approach to identify proteins showing altered levels in the AD brain. We studied the relationship between the protein with the highest increase in hippocampus, DEAD box Helicase 24 (DDX24), and AD pathology. We visualised DDX24 in the human brain and in a mouse model for Aβ42-induced AD pathology-AppNL-F-and studied the interaction between Aβ and DDX24 in primary neurons. Immunohistochemistry in the AD brain confirmed the increased levels and indicated an altered subcellular distribution of DDX24. Immunohistochemical studies in AppNL-F mice showed that the increase of DDX24 starts before amyloid pathology or memory impairment is observed. Immunocytochemistry in AppNL-F primary hippocampal neurons showed increased DDX24 intensity in the soma, nucleus and nucleolus. Furthermore, siRNA targeting of DDX24 in neurons decreased APP and Aβ42 levels, and the addition of Aβ42 to the medium reduced DDX24. In conclusion, we have identified DDX24 as a protein with a potential role in Aβ-induced AD pathology.

β-Amyloid peptide modulates peripheral immune responses and neuroinflammation in rats.

Alzheimer's disease (AD) is characterized by immune system dysregulation, impacting both central and peripheral immune responses. The study aimed to investigate the mechanism behind the neurotoxic effects of β-amyloid (Aβ) peptide in the rat brain including the study of neuroinflammation, neurodegeneration, and alterations in peripheral immune responses (PIR). The neuroinflammation brought on by Aβ1-42 and is unknown to influence PIR. Animal models were prepared, after 28 days, control, sham, and treated rats were anaesthetized and inflammatory markers of hippocampus and serum levels (reactive oxygen species, nitrite, tumor necrosis factor-α, and interleukin-1β), and some markers of PIR (splenic mononuclear cells or MNC, cytotoxicity and phagocytic index of the white blood cells leukocyte adhesion inhibition index or LAI), as well as polymorphonuclear cells of the spleen, were assessed. In addition to changes in peripheral immune responses, the present study found that AD rats had higher blood levels of inflammatory markers. Based on the study, the immune system irregularities observed in AD rats in the peripheral regions might be connected to neuroinflammation, which is facilitated by a compromised blood-brain barrier. Hence, it is viable to propose that the neuroinflammatory condition in rats with Aβ-induced AD could modify immune responses in the peripheral areas with significantly higher levels of inflammatory cytokines markers in the hippocampal tissue in Aβ-injected AD rats.

Flavonoids From Stems and Leaves of Scutellaria Baicalensis Georgi Improve Composited Aβ-Induced Alzheimer's Disease Model Rats' Memory and Neuroplasticity Disorders.

The study aims to investigate the effects and mechanism of flavonoids from stems and leaves of Scutellaria baicalensis Georgi (SSF) on the disorders in learning and memory and neuroplasticity induced by beta amyloid 25-35 (Aβ25-35) combined with aluminum trichloride (AlCl3) and human recombinant transfer factor-β1 (RHTGF-β1) (composited Aβ) in rats. A rat Alzheimer's disease (AD) model was established by intracerebroventricular injection of Aβ25-35 combined with AlCl3 and RHTGF-β1. The successful AD model of rats was screened with a Morris water maze. The successful model rats were randomly divided into a model group and three doses of SSF treated group. The Morris water maze was used to detect the rats' learning and memory abilities. The real-time fluorescence quantitative (qPCR) was applied to assay the mRNA expressions of CaM, CamkIV and Ferritin, as well as the neuroplasticity factors of HuB, HuC and HuD. The Western blotting was used to measure the protein expressions of CaM, CamkIV, HuB/D, HuC+HuD and Ferritin in the CaM-CamkIV-CREB signal pathway. Compared with the sham group, the abilities of learning and memory in the model group were significantly impaired (P<0.01), and the mRNA or protein expressions of CaM, CamkIV, HuB, HuC, HuD, HuB/D, HuC+HuD and Ferritin in CaM-CamkIV-CREB signal pathway were abnormally changed in model group. However, the three doses of SSF can differently ameliorate the impaired learning and memory and regulate the abnormal expressions of mRNA or protein in rats' CaM, CamkIV, HuB, HuC, HuD, HuB/D, HuC+HuD and Ferritin induced by composited Aβ. The improvement of SSF on the learning and memory disorder induced by composited Aβ is primarily derived from the positive regulation in the CaM-CamkIV-CREB signal pathway and activation in neuroplasticity.

Caffeic Acid, a Polyphenolic Micronutrient Rescues Mice Brains against Aβ-Induced Neurodegeneration and Memory Impairment.

Oxidative stress plays an important role in cognitive dysfunctions and is seen in neurodegeneration and Alzheimer's disease (AD). It has been reported that the polyphenolic compound caffeic acid possesses strong neuroprotective and antioxidant effects. The current study was conducted to investigate the therapeutic potential of caffeic acid against amyloid beta (Aβ1-42)-induced oxidative stress and memory impairments. Aβ1-42 (5 μL/5 min/mouse) was administered intracerebroventricularly (ICV) into wild-type adult mice to induce AD-like pathological changes. Caffeic acid was administered orally at 50 mg/kg/day for two weeks to AD mice. Y-maze and Morris water maze (MWM) behavior tests were conducted to assess memory and cognitive abilities. Western blot and immunofluorescence analyses were used for the biochemical analyses. The behavioral results indicated that caffeic acid administration improved spatial learning, memory, and cognitive abilities in AD mice. Reactive oxygen species (ROS) and lipid peroxidation (LPO) assays were performed and showed that the levels of ROS and LPO were markedly reduced in the caffeic acid-treated mice, as compared to Aβ-induced AD mice brains. Moreover, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were regulated with the administration of caffeic acid, compared to the Aβ-injected mice. Next, we checked the expression of ionized calcium-binding adaptor molecule 1 (Iba-1), glial fibrillary acidic proteins (GFAP), and other inflammatory markers in the experimental mice, which suggested enhanced expression of these markers in AD mice brains, and were reduced with caffeic acid treatment. Furthermore, caffeic acid enhanced synaptic markers in the AD mice model. Additionally, caffeic acid treatment also decreased Aβ and BACE-1 expression in the Aβ-induced AD mice model.

Effects of donepezil treatment on plasma and urine metabolites in amyloid beta-induced Alzheimer's disease rats

Accumulated clinical and biomedical evidence suggests that abnormalities in systemic metabolic processes such as fatty acid and amino acid metabolism can affect the brain function and behavior of various central nervous system diseases such as Alzheimer's disease (AD). In this study, metabolic profiling was used to investigate changes in plasma and urine metabolites following stereotactic injection of amyloid β (Aβ) and treatment with donepezil in rats. Aβ causes cognitive impairment, while donepezil treatment successfully improves memory impairment. Donepezil improves Aβ-induced plasma fatty acid and bile acid metabolism disorders, as well as Aβ-induced urine phenylalanine and tryptophan metabolism disorders in rats. More specifically, the plasma fatty acids improved by donepezil include alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, arachidonic acid, oleic acid, and palmitic acid, among others. Additionally, donepezil significantly restored the downregulation of bile acids such as ursodeoxycholic acid, cholic acid, and glycocholic acid caused by Aβ. As for urine metabolites, phenylacetylglycine, epinephrine, and other phenylalanine metabolites, as well as kynurenic acid, xanthurenic acid, and other tryptophan metabolites, were worsened by Aβ and improved by donepezil. These findings suggest that the cognitive impairment induced by Aβ and the improvement by donepezil are associated with changes in metabolic disorders in rats. This study provides basic data for the effects of Aβ and donepezil on plasma and urine metabolites in Aβ-induced AD rat models.

Royal jelly improves learning and memory deficits in an amyloid β-induced model of Alzheimer's disease in male rats: Involvement of oxidative stress.

Alzheimer's disease (AD) as the commonest type of dementia is associated with the cognitive function failure. Oxidative stress performs an essential role in the progression of AD. Royal jelly (RJ) is a natural product of bees with antioxidant and anti-inflammatory properties. The present research aimed to investigate the possible protective effect of RJ on learning and memory in a rat model of Aβ-induced AD. Forty male adult Wistar rats were equally distributed into five groups: control, sham-operated, Aβ (receiving intracerebroventricular (ICV) injection of amyloid beta (Aβ1-40)), Aβ + RJ 50mg/kg, and Aβ + RJ 100mg/kg. RJ was administered daily post-surgery by oral gavage for four weeks. Behavioral learning and memory were examined using the novel object recognition (NOR) and passive avoidance learning (PAL) tests. Also, oxidative stress markers, such as malondialdehyde (MDA), total oxidant status (TOS) and total antioxidant capacity (TAC), were assessed in the hippocampus. Aβ reduced step-through latency (STLr) and increased time spent in the dark compartment (TDC) in the PAL task and also decreased discrimination index in the NOR test. Administration of RJ ameliorated the Aβ-related memory impairment in both NOR and PAL tasks. Aβ decreased TAC and increased MDA and TOS levels in the hippocampus, whereas RJ administration reversed these Aβ-induced alterations. Our results indicated that RJ has the potential to ameliorate learning and memory impairment in the Aβ model of AD via attenuating oxidative stress.

Differential modulation of alpha 7 nicotinic achrs by picomolar vs. high nanomolar or micromolar concentrations of amyloid beta 42 peptide.

High concentrations (0.1-1.0 μM) of soluble oligomeric amyloid beta peptide(s) [Aβ] inhibit activation of α7 nAChRs. This may contribute to Alzheimer's Disease (AD) neuropathology, since α7 Rs play important roles in learning and memory. Thus, α7 Rs may be important targets for attenuating Aβ-induced AD cognitive declines. In contrast to the synapto-/neuro-toxic effects of high Aβ concentration observed in AD brains, several studies suggest that the low (pM) Aβ concentrations present in healthy non-AD brains are critical for normal learning and memory. These beneficial effects are dependent on expression of α7, suggesting that pM Aβ's salutary effects are mediated by α7 Rs, possibly as an agonist or PAM at α7 Rs. The nature of the Aβ-α7 R interaction, however, has not been fully characterized. In this study we found that 10-100 pM Aβ produced a ∼1.7- to 2.6-fold facilitation of ACh-elicited α7 currents, but did not elicit α7 currents directly. When applied with the type II PAM PNU 120596, 100 pM Aβ occluded the facilitation of peak current produced by PNU 120596, suggesting that Aβ and PNU 120596 potentiated α7 Rs through the same or overlapping allosteric site(s). This conclusion was further supported by analysis of a mutant α7 R containing a missense mutation in a critical amino acid for potentiation by PAMs (M276L in TM 2). Peak current facilitation by 100 pM Aβ was abolished for this mutant. Surprisingly, this mutation also abolished the inhibitory effects of high (0.1-1.0 μM) Aβ concentrations. This suggests that inhibitory (nM to µM) and facilitatory (pM) Aβ concentrations exert their opposing effects on α7 R activity via the same or overlapping sites, rather than at distinct allosteric sites.

The Protective Effects of Policosanol on Learning and Memory Impairments in a Male Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD), the most common form of dementia, is characterized by a progressive decline in cognitive performance and memory formation. The present study was designed to investigate the effect of policosanol (PCO) on cognitive function, oxidative-antioxidative status, and amyloid-beta (Aβ) plaque formation in an AD rat model induced by intracerebroventricular (ICV) injection of Aβ1-40. Healthy adult male Wistar rats were randomly divided into seven groups: control, sham (5 μL, ICV injection of phosphate-buffered saline), AD model (5 μL, ICV injection of Aβ), acacia gum (50mg/kg, 8weeks, gavage), PCO (50mg/kg, 8weeks, gavage), AD + acacia gum (50mg/kg, 8weeks, gavage), and AD + PCO (50mg/kg, 8weeks, gavage). During the ninth and tenth weeks of the study, the cognitive function of the rats was assessed by commonly used behavioral paradigms. Subsequently, oxidative-antioxidative status was examined in the serum. Moreover, compact Aβ plaques were detected by Congo red staining. The results showed that injection of Aβ impaired recognition memory in the novel object recognition test, reduced the spatial cognitive ability in the Morris water maze, and alleviated retention and recall capability in the passive avoidance task. Additionally, injection of Aβ resulted in increased total oxidant status, decreased total antioxidant capacity, and enhanced Aβ plaque formation in the rats. Intriguingly, PCO treatment improved all the above-mentioned neuropathological changes in the Aβ-induced AD rats. The results suggest that PCO improves Aβ-induced cognitive decline, possibly through modulation of oxidative-antioxidative status and inhibition of Aβ plaque formation.

Treadmill exercise improve recognition memory by TREM2 pathway to inhibit hippocampal microglial activation and neuroinflammation in Alzheimer's disease model

Alzheimer's disease-related cognition impairment is correlated with increased neuroinflammation. Studies show that physical exercises improve cognitive function and regulate neuroinflammation. However, no sufficient studies have been performed to directly observe the mechanism of exercise-related effects on microglia and neuroinflammation, in association with memory function under Alzheimer's disease. This study aims to explore the relationship of TREM2, microglia activation and neuroinflammation in the development of Alzheimer's disease, followed by investigating why physical exercises improve cognition in the Alzheimer's disease model by means of the adeno-associated virus (AAV) injection. We found that: 1) Recognition memory impairment in Aβ-induced Alzheimer's disease model was associated with the reduction in TREM2 which induced microglial activation and neuroinflammation; 2) Exercise activated the TREM2 pathway, which was necessary for inhibiting microglial activation and neuroinflammation, leading to improved recognition memory in the Alzheimer's disease model. Together, the improvement of AD-associated recognition memory by exercises is associated with up-regulation of the TREM2 pathway which promotes the phenotypic conversion of microglia and decreases the level of neuroinflammation.

Cannabidiol protects against Alzheimer's disease in C. elegans via ROS scavenging activity of its phenolic hydroxyl groups

Recent discoveries have implicated the potential of Cannabidiol (CBD) in the prevention of Alzheimer's disease (AD). However, how CBD affects such neurodegenerative disorders remains unclear. Herein, Caenorhabditis elegans (C. elegans) was used as the model organism to elucidate the mechanism by which CBD ameliorates AD in vivo. CBD was found to alleviate the progression of Aβ-induced AD but not tau protein-induced AD or α-syn-induced Parkinson's disease. CBD inhibited the aggregation of Aβ in C. elegans. However, CBD failed to prevent the formation of β-sheet aggregation in vitro. Moreover, CBD was found to scavenge reactive oxygen species (ROS) in vivo without inducing the overexpression of antioxidative genes. In addition, CBD treatment enhanced the worm resistance to oxidative stress, which was independent of the classical transcription factors DAF-16 and SKN-1. These results supported that the in vivo antioxidative activity of CBD was most likely due to its intrinsic antioxidative property. Furthermore, the phenolic hydroxyl groups of CBD were found to be critical for scavenging ROS in vitro and in vivo, alleviating the aggregation of Aβ in vivo, and ameliorating Aβ-associated neurotoxicity. These studies show that CBD protects against AD in C. elegans via the ROS scavenging activity of its phenolic hydroxyl groups, which provides insight for further structure-activity relationship studies of CBD as an AD therapeutic.

Reduction of advanced tau-mediated memory deficits by the MAP kinase p38γ.

Hyperphosphorylation of the neuronal tau protein contributes to Alzheimer's disease (AD) by promoting tau pathology and neuronal and cognitive deficits. In contrast, we have previously shown that site-specific tau phosphorylation can inhibit toxic signals induced by amyloid-β (Aβ) in mouse models. The post-synaptic mitogen-activated protein (MAP) kinase p38γ mediates this site-specific phosphorylation on tau at Threonine-205 (T205). Using a gene therapeutic approach, we draw on this neuroprotective mechanism to improve memory in two Aβ-dependent mouse models of AD at stages when advanced memory deficits are present. Increasing activity of post-synaptic kinase p38γ that targets T205 in tau reduced memory deficits in symptomatic Aβ-induced AD models. Reconstitution experiments with wildtype human tau or phosphorylation-deficient tauT205A showed that T205 modification is critical for downstream effects of p38γ that prevent memory impairment in APP-transgenic mice. Furthermore, genome editing of the T205 codon in the murine Mapt gene showed that this single side chain in endogenous tau critically modulates memory deficits in APP-transgenic Alzheimer's mice. Ablating the protective effect of p38γ activity by genetic p38γ deletion in a tau transgenic mouse model that expresses non-pathogenic tau rendered tau toxic and resulted in impaired memory function in the absence of human Aβ. Thus, we propose that modulating neuronal p38γ activity serves as an intrinsic tau-dependent therapeutic approach to augment compromised cognition in advanced dementia.

Anti-PrP monoclonal antibody as a novel treatment for neurogenesis in mouse model of Alzheimer's disease.

BackgroundAlzheimer's disease (AD) is the most common degenerative disease characterized by cognitive impairment, memory decline, and language disorder for which there is no effective treatment. Neurogenesis has been indicated in AD and may play an important role in the pathogenesis of AD. Targeting this pathway is a new idea for the treatment of the disease. A recent study reveals that the cellular prion protein (PrP), a receptor for Aβ oligomers, regulates neurogenesis, and its elevated expression is related to cell differentiation. The aim of the present study was to investigate the neuroprotective effects of 6D11 (PrP monoclonal antibody) via neurogenesis promotion in APP/PS1 transgenic mice and Aβ‐induced cell model of AD.MethodsIn the present study, 9‐month‐old male APP/PS1 mice were injected with 6D11. Then, the Morris water maze was used to examine the spatial learning and memory abilities of the mice in both groups, and immunostained was used to assess the level of Aβ, neurogenesis, and neural stem cells (NSCs) differentiation.Results6D11 attenuated cognitive deficits in APP/PS1 transgenic mice, which was accompanied by a decrease of the deposition of Aβ. In addition, 6D11 treatment promoted differentiation of the existing hippocampal cells to neurons.ConclusionsOur findings confirmed that 6D11 has a therapeutic effect in APP/PS1 transgenic AD mouse model and Aβ‐induced AD cell model, and the effect exerted via increase of neurogenesis and cell differentiation by transduction of Aβ peptide signal.

Inhibition of sEH via stabilizing the level of EETs alleviated Alzheimer's disease through GSK3β signaling pathway

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by dementia. Inhibition of soluble epoxide hydrolase (sEH) regulates inflammation involving in central nervous system (CNS) diseases. However, the exactly mechanism of sEH in AD is still unclear. In this study, we evaluated the vital role of sEH in amyloid beta (Aβ)-induced AD mice, and revealed a possible molecular mechanism for inhibition of sEH in the treatment of AD. The results showed that the sEH expression and activity were remarkably increased in the hippocampus of Aβ-induced AD mice. Chemical inhibition of sEH by TPPU, a selective sEH inhibitor, alleviated spatial learning and memory deficits, and elevated levels of neurotransmitters in Aβ-induced AD mice. Furthermore, inhibition of sEH could ameliorate neuroinflammation, neuronal death, and oxidative stress via stabilizing the in vivo level of epoxyeicosatrienoic acids (EETs), especially 8,9-EET and 14,15-EET, further resulting in the anti-AD effect through the regulation of GSK3β-mediated NF-κB, p53, and Nrf2 signaling pathways. These findings revealed the underlying mechanism of sEH as a potential therapeutic target in treatment of AD.

A comparative study of the effects of phosphatidylserine rich in DHA and EPA on Aβ-induced Alzheimer's disease using cell models.

Alzheimer's disease (AD) is an age-dependent, irreversible neurodegenerative disease, and one of the pathological features is amyloid-β (Aβ) deposition. Previous studies have shown that phosphatidylserine (PS) enriched with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) exhibited significant effects in preventing and alleviating the progress of AD. However, no studies have focused on the differences in the preventive effects on AD between EPA-PS and DHA-PS. Here, the effects of EPA-PS and DHA-PS on Aβ production, Aβ-induced neurotoxicity and Aβ clearance have been studied. The results show that DHA-PS significantly reduced Aβ production in CHO-APP/PS1 cells compared to EPA-PS. Moreover, both EPA-PS and DHA-PS significantly protected the primary hippocampal neurons against Aβ-induced toxicity by inhibiting the mitochondrial-dependent apoptotic pathway and phosphorylation of JNK and p38. Compared to DHA-PS, EPA-PS administration significantly improved the Aβ phagocytic capacity of BV2 cells. In addition, EPA-PS and DHA-PS significantly promoted the neurite outgrowth of primary hippocampal neurons. These findings might provide dietary guidance for the prevention of AD as well as a reference for the development of related functional foods.

Oral Administration of Gintonin Protects the Brains of Mice against Aβ-Induced Alzheimer Disease Pathology: Antioxidant and Anti-Inflammatory Effects.

The study was aimed at analyzing the protective effects of gintonin in an amyloid beta- (Aβ-) induced Alzheimer's disease (AD) mouse model. For the development of the Aβ-induced AD mouse model, the amyloid-β (Aβ1-42) peptide was stereotaxically injected into the brains of mice. Subsequently, gintonin was administered at a dose of 100 mg/kg/day/per oral (p.o) for four weeks daily, and its effects were evaluated by using western blotting, fluorescence analysis of brain sections, biochemical tests, and memory-related behavioral evaluations. To elucidate the effects of gintonin at the mechanistic level, the activation of endogenous antioxidant mechanisms, as well as the activation of astrocytes, microglia, and proinflammatory mediators such as nuclear factor erythroid 2-related factor 2 (NRF-2) and heme oxygenase-1 (HO-1), was evaluated. In addition, microglial cells (BV-2 cells) were used to analyze the effects of gintonin on microglial activation and signaling mechanisms. Collectively, the results suggested that gintonin reduced elevated oxidative stress by improving the expression of NRF-2 and HO-1 and thereby reducing the generation of reactive oxygen species (ROS) and lipid peroxidation (LPO). Moreover, gintonin significantly suppressed activated microglial cells and inflammatory mediators in the brains of Aβ-injected mice. Our findings also indicated improved synaptic and memory functions in the brains of Aβ-injected mice after treatment with gintonin. These results suggest that gintonin may be effective for relieving AD symptoms by regulating oxidative stress and inflammatory processes in a mouse model of AD. Collectively, the findings of this preclinical study highlight and endorse the potential, multitargeted protective effects of gintonin against AD-associated oxidative damage, neuroinflammation, cognitive impairment, and neurodegeneration.

ROS-responsive and multifunctional anti-Alzheimer prodrugs: Tacrine-ibuprofen hybrids via a phenyl boronate linker.

Current drugs available in clinic for Alzheimer's disease (AD) treatment can only alleviate disease symptoms without clearly curing or delaying the process of AD. And some AD drugs failed in Phase III clinical trials are only focused on targeting amyloid-β (Aβ). Therefore, an alternative strategy in AD drug design is meaningful to be involved in the multiple pathogenic factors which can affect each other at multiple levels. Herein, we report a series of ROS-responsive prodrugs based on multi-target-directed ligands (MTDLs) approach, which can specifically release tacrine derivatives and ibuprofen under oxidation of ROS and show acetylcholinesterase (AChE)-inhibiting, neuron-protective and anti-inflammatory effects in extracellular or intracellular assays. Related biological study illustrated that compound 22 was able to permeate blood-brain-barrier (BBB) showing little hepatotoxicity in comparison to tacrine. Besides, 22 hinted a therapeutic clue in AD-treatment by regulating proinflammatory factors (IL-1β and TNF-α) and apoptosis related proteins (Bax, Bcl-2 and cleaved caspase-3). Further spatial memory assays in Aβ-induced AD model showed that 22 enhanced the ability of learning and memory. Our study proves that the strategy of ROS-responsive prodrugs has promise for AD treatments in future and offers a way for AD drug development.

Liquiritigenin Decreases Aβ Levels and Ameliorates Cognitive Decline by Regulating Microglia M1/M2 Transformation in AD Mice.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is currently incurable. Amyloid β protein (Aβ) deposition is the main pathogenesis of AD, and many studies have shown that Aβ accumulation is toxic to neurons, leading to the inflammatory reaction, neuronal apoptosis, and neurofibrillary tangles. Thus, reducing Aβ levels might be a potential therapeutic strategy for AD. Liquiritigenin (LG), a dihydroflavone monomer compound extracted from natural plant licorice, has a variety of biological activities such as antioxidant, anti-tumor, anti-inflammatory and anti-virus. However, the exact function of LG in the pathogenesis of AD is elusive. Here, we reported that LG could significantly attenuate neuronal apoptosis in Aβ-induced N2A cells and APP/PS1 transgenic mice. Our in vivo and in vitro studies revealed that LG could alleviate the inflammation response, reflected by the reduction of NLRP3 and cleaved caspase-1. Meanwhile, we also found that LG was able to shift M1 type microglia towards M2 type microglia in Aβ-induced BV2 cells and AD mice. Furthermore, LG could reduce the Aβ levels by decreasing APP processing and accelerating Aβ clearance in AD mice. More importantly, daily treatment of LG (30mg/kgday) for 90days dramatically ameliorated the spatial learning and memory of AD mice. Taken together, these results suggest that LG can reduce the Aβ levels by regulating the M1/M2 transformation of microglia, thereby reversing memory decline during AD development, suggesting that LG may be a potential therapeutic agent for treating AD.

Reduction of advanced tau-mediated memory deficits by the MAP kinase p38γ.

Hyperphosphorylation of the neuronal tau protein contributes to Alzheimer's disease (AD) by promoting tau pathology and neuronal and cognitive deficits. In contrast, we have previously shown that site-specific tau phosphorylation can inhibit toxic signals induced by amyloid-β (Aβ) in mouse models. The post-synaptic mitogen-activated protein (MAP) kinase p38γ mediates this site-specific phosphorylation on tau at Threonine-205 (T205). Using a gene therapeutic approach, we draw on this neuroprotective mechanism to improve memory in two Aβ-dependent mouse models of AD at stages when advanced memory deficits are present. Increasing activity of post-synaptic kinase p38γ that targets T205 in tau reduced memory deficits in symptomatic Aβ-induced AD models. Reconstitution experiments with wildtype human tau or phosphorylation-deficient tauT205A showed that T205 modification is critical for downstream effects of p38γ that prevent memory impairment in APP-transgenic mice. Furthermore, genome editing of the T205 codon in the murine Mapt gene showed that this single side chain in endogenous tau critically modulates memory deficits in APP-transgenic Alzheimer's mice. Ablating the protective effect of p38γ activity by genetic p38γ deletion in a tau transgenic mouse model that expresses non-pathogenic tau rendered tau toxic and resulted in impaired memory function in the absence of human Aβ. Thus, we propose that modulating neuronal p38γ activity serves as an intrinsic tau-dependent therapeutic approach to augment compromised cognition in advanced dementia.

Effect of the King Oyster Culinary-Medicinal Mushroom Pleurotus eryngii (Agaricomycetes) Basidiocarps Powder to Ameliorate Memory and Learning Deficit in Ability in Aβ-Induced Alzheimer's Disease C57BL/6J Mice Model

One of the major causes of Alzheimer's disease (AD) is oxidative stress, which accelerates β-amyloid peptide (AP) plaque and neurofibrillary tangle accumulation in the brain. Pleurotus eryngii is known to be rich in antioxidants, including ergothioneine, adenosine, and polyphenol, which can reduce oxidative stress-related aging. The aim of this study was to investigate the proximate and functional composition of P. eryngii, and evaluate the cognitive effects of low (LPE), medium (MPE), and high (HPE) P. eryngii dosages in an Aβ-induced Alzheimer's disease C57BL/6J mouse model. Mice fed P. eryngii for six weeks showed no adverse effects on body weight gain, food intake efficiency, serum biochemical parameters, and liver and kidney histopathological features. The relative brain weight was significantly lower in Aβ-injected mice (p < 0.05). Further, P. eryngii was shown to delay brain atrophy. Reference memory behavioral tasks showed that LPE, MPE, and HPE significantly decreased escape latency (49-85%) and distance (53-69%, p < 0.05). Probe and T-maze tasks showed that P. eryngii potently ameliorated memory deficit in mice. An AD pathology index analysis showed that P. eryngii significantly decreased levels of brain phosphorylated τ-protein, Aβ plaque deposition, malondialdehyde, and protein carbonyl (p < 0.05). P. eryngii may therefore promote memory and learning capacity in an Aβ-induced AD mouse model.