Effect of total flavonoids of Dracocephalum moldavica L. On neuroinflammation in Alzheimer's disease model amyloid-ß (Aß1-42)-peptide-induced astrocyte activation.

One of the main pathological features noted in Alzheimer's disease (AD) is the presence of plagues of aggregated ß-amyloid (Aß1-42)-peptides. Excess deposition of amyloid-ß oligomers (AßO) are known to promote neuroinflammation. Sequentially, following neuroinflammation astrocytes become activated with cellular characteristics to initiate activated astrocytes. The purpose of this study was to determine whether total flavonoids derived from Dracocephalum moldavica L. (TFDM) inhibited Aß1-42-induced damage attributed to activated C8-D1A astrocytes. Western blotting and ELISA were used to determine the expression of glial fibrillary acidic protein (GFAP), and complement C3 to establish the activation status of astrocytes following induction from exposure to Aß1-42. Data demonstrated that stimulation of C8-D1A astrocytes by treatment with 40 µM Aß1-42 for 24 hr produced significant elevation in protein expression and protein levels of acidic protein (GFAP) and complement C3 accompanied by increased expression and levels of inflammatory cytokines. Treatment with TFDM or the clinically employed drug donepezil in AD therapy reduced production of inflammatory cytokines, and toxicity initiated following activation of C8-D1A astrocytes following exposure to Aß1-42. Therefore, TFDM similar to donepezil inhibited inflammatory secretion in reactive astrocytes, suggesting that TFDM may be considered as a potential compound to be utilized in AD therapy.

Galectin-9 and Tim-3 are upregulated in response to microglial activation induced by the peptide Amyloid-ß (25-35).

Galectins are a group of ß-galactoside-binding lectins associated with regulating immunological response. In the brains of AD patients and 5xFAD (familial AD) mice, galectin-3 (Gal-3) was highly upregulated and found to be expressed in microglia associated with Aß plaques. However, the participation of other galectins, specifically galectin-9 (Gal-9) and T-cell immunoglobulin and mucin domain 3 (Tim-3) receptors, are unknown in the inflammatory response. The experimental model of the Aß25-35 peptide will allow us to study the mechanisms of neuroinflammation and describe the changes in the expression of the Gal-9 and Tim-3 receptor. This study aimed to evaluate whether Aß25-35 peptide administration into the lateral ventricles of rats upregulated Gal-9 and Tim-3 implicated in the modulation of neuroinflammation. The vehicle or Aß25-35 peptide (1 µg/µL) was bilaterally administered into the lateral ventricles of the rat, and control group. After the administration of the Aß25-35 peptide, animals were tested for learning (day 29) and spatial memory (day 30) in the novel object recognition test (NOR). On day 31, hippocampus was examined for morphological changes by Nilss stain, biochemical changes by NO2 and MDA, immunohistochemical analysis by astrocytes (GFAP), microglia (Iba1), Gal-9 and Tim-3, and western blot. Our results show the administration of the Aß25-35 peptide into the lateral ventricles of rats induce memory impairment in the NOR by increases the oxidative stress and inflammatory response. This result is associated with an upregulation of Gal-9 and Tim-3 predominantly detected in the microglia cells of Aß25-35-treated rats with respect to the control group. Gal-9 and Tim-3 are upregulated in activated microglia that could modulate the inflammatory response and damage in neurodegenerative processes induced by the Aß25-35 peptide. Therefore, we suggest that Gal-9 and Tim-3 participate in the inflammatory process induced by the administration of the Aß25-35 peptide.

Liver-specific adiponectin gene therapy suppresses microglial NLRP3-inflammasome activation for treating Alzheimer's disease.

Adiponectin (APN) is an adipokine which predominantly expresses in adipocytes with neuroprotective and anti-inflammatory effects. We have recently indicated that circulatory trimeric APN can enter the brain by crossing the blood-brain barrier (BBB) and modulate microglia-mediated neuroinflammation. Here, we found that the microglial NLR family pyrin domain containing 3 (NLRP3)-inflammasome activation was exacerbated in APN-/-5xFAD mice in age-dependent manner. The focus of this study was to develop a new and tractable therapeutic approach for treating Alzheimer's disease (AD)-related pathology in 5xFAD mice using peripheral APN gene therapy. We have generated and transduced adeno-associated virus (AAV2/8) expressing the mouse mutated APN gene (APNC39S) into the liver of 5xFAD mice that generated only low-molecular-weight trimeric APN (APNTri). Single dose of AAV2/8-APNC39S in the liver increased circulatory and cerebral APN levels indicating the overexpressed APNTri was able to cross the BBB. Overexpression of APNTri decreased both the soluble and fibrillar Aß in the brains of 5xFAD mice. AAV2/8-APNTri treatment reduced Aß-induced IL-1ß and IL-18 secretion by suppressing microglial NLRP3-inflammasome activation. The memory functions improved significantly in AAV-APNTri-treated 5xFAD mice with reduction of dystrophic neurites. These findings demonstrate that peripheral gene delivery to overexpress trimeric APN can be a potential therapy for AD.

Amyloid ß interferes with wound healing of brain microvascular endothelial cells by disorganizing the actin cytoskeleton.

Cerebral amyloid angiopathy (CAA) is a disease in which amyloid ß (Aß) is deposited in the cerebral blood vessels, reducing compliance, tearing and weakening of vessel walls, leading to cerebral hemorrhage. The mechanisms by which Aß leads to focal wall fragmentation and intimal damage are not well understood. We analyzed the motility of human brain microvascular endothelial cells (hBMECs) in real-time using a wound-healing assay. We observed the suppression of cell migration by visualizing Aß aggregation using quantum dot (QD) nanoprobes. In addition, using QD nanoprobes and a SiR-actin probe, we simultaneously observed Aß aggregation and F-actin organization in real-time for the first time. Aß began to aggregate at the edge of endothelial cells, reducing cell motility. In addition, Aß aggregation disorganized the actin cytoskeleton and induced abnormal actin aggregation. Aß aggregated actively in the anterior group, where cell motility was active. Our findings may be a first step toward explaining the mechanism by which Aß causes vascular wall fragility, bleeding, and rebleeding in CAA.

Novel Flavonol Alkaloids in Green Tea: Synthesis, Detection, and Anti-Alzheimer's Disease Effect in a Transgenic Caenorhabditis elegans CL4176 Model.

Novel N-ethy-2-pyrrolidinone-substituted flavonols, myricetin alkaloids A-C (1-3), quercetin alkaloids A-C (4a, 4b, and 5), and kaempferol alkaloids A and B (6 and 7), were prepared from thermal reaction products of myricetin, quercetin, kaempferol─l-theanine, respectively. We used HPLC-ESI-HRMS/MS to detect 1-7 in 14 cultivars of green tea and found that they were all present in "Shuchazao," "Longjing 43", "Fudingdabai", and "Zhongcha 108" green teas. The structures of 1-4 and 6 were determined by extensive 1D and 2D NMR spectroscopies. These flavonol alkaloids along with their skeletal flavonols were assessed for anti-Alzheimer's disease effect based on molecular docking, acetylcholinesterase inhibition, and the transgenic Caenorhabditis elegans CL4176 model. Compound 7 strongly binds to the protein amyloid ß (Aß1-42) through hydrogen bonds (BE: -9.5 kcal/mol, Ki: 114.3 nM). Compound 3 (100 µM) is the strongest one in significantly extending the mean lifespan (13.4 ± 0.5 d, 43.0% promotion), delaying the Aß1-42-induced paralysis (PT50: 40.7 ± 1.9 h, 17.1% promotion), enhancing the locomotion (140.0% promotion at 48 h), and alleviating glutamic acid (Glu)-induced neurotoxicity (153.5% promotion at 48 h) of CL4176 worms (p < 0.0001).

Radiation Therapy in Alzheimer's Disease: A Systematic Review.

PURPOSE: Pathophysiological hallmarks of Alzheimer's disease (AD) include extracellular amyloid plaques and intracellular neurofibrillary tangles. Recent studies also demonstrated a role of neuroinflammation in the progression of the disease. Clinical trials and animal studies using low-dose radiation therapy (LDRT) have shown therapeutic potential for AD. This systematic review summarizes the current evidence on the use of LDRT for the treatment of AD, outlines potential mechanisms of action, and discusses current challenges in the planning of future trials. METHODS AND MATERIALS: A systematic review of human and animal studies as well as registered clinical trials describing outcomes for RT in the treatment of AD was conducted. We followed the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles published until July 1, 2023, were included. RESULTS: The initial search yielded 993 articles. After the removal of duplicates and ineligible publications, a total of 16 (12 animal, 4 human) studies were included. Various dose regimens were utilized in both animal and human trials. The results revealed that LDRT reduced the number of amyloid plaques and neurofibrillary tangles, and it has a role in the regulation of genes and protein expression involved in the pathological progression of AD. LDRT has demonstrated reduced astro- and microgliosis, anti-inflammatory and neuroprotective effects, and an alleviation of symptoms of cognitive deficits in animal models. Most studies in humans suggested improvements in cognition and behavior. None of the trials or studies described significant (>grade 2) toxicity. CONCLUSIONS: Preclinical studies, animal studies, and early clinical trials in humans have shown a promising role for LDRT in the treatment of AD pathologies, although the underlying mechanisms are yet to be fully explored. Phase I/II/III trials are needed to assess the long-term safety, efficacy, and optimal treatment parameters of LDRT in AD treatment.

MCC950 reduces autophagy and improves cognitive function by inhibiting NLRP3-dependent neuroinflammation in a rat model of Alzheimer's disease.

Alzheimer's disease (AD) is the seventh most common cause of mortality and one of the major causes of disability and vulnerability in the elderly. AD is characterized by gradual cognitive deterioration, the buildup of misfolded amyloid beta (Aß) peptide, and the generation of neurofibrillary tangles. Despite enormous scientific progress, there is no effective cure for AD. Thus, exploring new treatment options to stop AD or at least slow down its progress is important. In this study, we investigated the potential therapeutic effects of MCC950 on NLRP3-mediated inflammasome-driven inflammation and autophagy in AD. Rats treated with streptozotocin (STZ) exhibited simultaneous activation of the NLRP3 inflammasome and autophagy, as confirmed by Western blot, immunofluorescence, and co-immunoprecipitation analyses. MCC950, a specific NLRP3 inhibitor, was intraperitoneally administered (50 mg/kg body weight) to rats with AD-like symptoms induced by intracerebroventricular STZ injections (3 mg/kg body weight). MCC950 effectively suppressed STZ-induced cognitive impairment and anxiety by inhibiting NLRP3-dependent neuroinflammation. Moreover, our findings indicate that MCC950 exerts neuroprotective effects by attenuating autophagy in neuronal cells. The inhibiting effects of MCC950 on inflammasome activation and autophagy were reproduced in vitro, provding further mechansistic insights into MCC950 therapeutic action. Our findings suggest that MCC950 impedes the progression of AD and may also improve cognitive function through the mitigation of autophagy and NLRP3 inflammasome inhibition.

Irisin limits amyloid-ß buildup in Alzheimer's disease.

Mounting evidence suggests that physical exercise protects the brain against neurodegenerative disease. In a recent paper in Neuron, Kim et al. reported that the exercise-induced hormone irisin curbs amyloid-ß buildup by promoting secretion of astrocyte-derived neprilysin. These findings may help explain the neuroprotection by irisin and exercise in Alzheimer's disease.

Different paradigms of transcranial electrical stimulation induce structural changes in the CA1 region of the hippocampus in a rat model of Alzheimer's disease.

One of the prominent sign of Alzheimer's disease (AD) is structural changes in the hippocampus. Recently, the new methods used to treat this disease is transcranial electrical stimulation (tES). This study evaluated the effect of four primary standards of tES, including tDCS, tACS, tRNS, and tPCS on beta-amyloid 25-35 (Aß25-35)-induced structural changes in the CA1 region of hippocampus in male rats. For this purpose, rats weighing 250-275 g were selected, the cannula was embedded reciprocally into the hippocampi. Aß25-35 (5 µg/ 2.5 ml/ day) was infused reciprocally for four continuous days.Then, animals were then given tES for 6 days.Subsequently, structural changes in the hippocampal CA1 were evaluated using the stereological method. Aß25-35 resulted in loss of neurons (P < 0.01) and decreased hippocampal volume (P < 0.05). However, the administration of tES paradigms prevented these changes. The results proposed that through the improvement of hippocampal cell number and volume, tES paradigms can retain efficiency in remediating structural impairments in AD. From this, it can be concluded that other tES paradigms besides tDCS can also be considered for the treatment of AD.

Notoginsenoside R1 ameliorates the inflammation induced by amyloid­ß by suppressing SphK1­mediated NF­κB activation in PC12 cells.

Alzheimer's disease (AD) is the most common type of age­related dementia, and causes progressive memory degradation, neuronal loss and brain atrophy. The pathological hallmarks of AD consist of amyloid­ß (Aß) plaque accumulation and abnormal neurofibrillary tangles. Amyloid fibrils are constructed from Aß peptides, which are recognized to assemble into toxic oligomers and exert cytotoxicity. The fibrillar Aß­protein fragment 25­35 (Aß25­35) induces local inflammation, thereby exacerbating neuronal apoptosis. Notoginsenoside R1 (NGR1), one of the primary bioactive ingredients isolated from Panax notoginseng, exhibits effective anti­inflammatory and anti­oxidative activities. However, NGR1 pharmacotherapies targeting Aß­induced inflammation and cell injury cascade remain to be elucidated. The present study investigated the effect and mechanism of NGR1 in Aß25­35­treated PC12 cells. NGR1 doses between 250 and 1,000 µg/ml significantly increased cell viability suppressed by 20 µM Aß25­35 peptide treatment. Notably, the present study demonstrated that Aß25­35 peptide­induced sphingosine kinase 1 (SphK1) signaling activation was reduced after NGR1 treatment, further inhibiting the downstream NF­κB inflammatory signaling pathway. In addition, administration of SphK1 inhibitor II (SKI­II), a SphK1 inhibitor, also significantly reduced Aß25­35 peptide­induced apoptosis and the ratio of NF­κB p­p65/p65. Furthermore, SphK1 knockdown in PC12 cells using small interfering RNA alleviated Aß­induced cell apoptosis and inflammation, suggesting a pivotal role of SphK1 signaling in the anti­inflammatory effect of NGR1. In summary, NGR1 alleviated inflammation and apoptosis stimulated by Aß25­35 by inhibiting the SphK1/NF­κB signaling pathway and may be a promising agent for future AD treatment.

Transcriptomic analyses reveal proinflammatory activation of human brain microvascular endothelial cells by aging-associated peptide medin and reversal by nanoliposomes.

Medin is a common vascular amyloidogenic peptide recently implicated in Alzheimer's disease (AD) and vascular dementia and its pathology remains unknown. We aim to identify changes in transcriptomic profiles and pathways in human brain microvascular endothelial cells (HBMVECs) exposed to medin, compare that to exposure to ß-amyloid (Aß) and evaluate protection by monosialoganglioside-containing nanoliposomes (NL). HBMVECs were exposed for 20 h to medin (5 µM) without or with Aß(1-42) (2 µM) or NL (300 µg/mL), and RNA-seq with signaling pathway analyses were performed. Separately, reverse transcription polymerase chain reaction of select identified genes was done in HBMVECs treated with medin (5 µM) without or with NFκB inhibitor RO106-9920 (10 µM) or NL (300 µg/mL). Medin caused upregulation of pro-inflammatory genes that was not aggravated by Aß42 co-treatment but reversed by NL. Pathway analysis on differentially expressed genes revealed multiple pro-inflammatory signaling pathways, such as the tumor necrosis factor (TNF) and the nuclear factor-κB (NFkB) signaling pathways, were affected specifically by medin treatment. RO106-9920 and NL reduced medin-induced pro-inflammatory activation. Medin induced endothelial cell pro-inflammatory signaling in part via NFκB that was reversed by NL. This could have potential implications in the pathogenesis and treatment of vascular aging, AD and vascular dementia.

Amyloid-ß Effects on Peripheral Nerve: A New Model System.

Although there are many biochemical methods to measure amyloid-ß (Aß)42 concentration, one of the critical issues in the study of the effects of Aß42 on the nervous system is a simple physiological measurement. The in vitro rat sciatic nerve model is employed and the nerve action potential (NAP) is quantified with different stimuli while exposed to different concentrations of Aß42. Aß42 predominantly reduces the NAP amplitude with minimal effects on other parameters except at low stimulus currents and short inter-stimulus intervals. The effects of Aß42 are significantly concentration-dependent, with a maximum reduction in NAP amplitude at a concentration of 70 nM and smaller effects on the NAP amplitude at higher and lower concentrations. However, even physiologic concentrations in the range of 70 pM did reduce the NAP amplitude. The effects of Aß42 became maximal 5-8 h after exposure and did not reverse during a 30 min washout period. The in vitro rat sciatic nerve model is sensitive to the effects of physiologic concentrations of Aß42. These experiments suggest that the effect of Aß42 is a very complex function of concentration that may be the result of amyloid-related changes in membrane properties or sodium channels.

TSPO Modulates Oligomeric Amyloid-ß-Induced Monocyte Chemotaxis: Relevance for Neuroinflammation in Alzheimer's Disease.

BACKGROUND: Neuroinflammation is one of the cardinal mechanisms of Alzheimer's disease (AD). with amyloid-ß (Aß) playing a critical role by activating microglia to produce soluble inflammatory mediators, including several chemokines. Peripheral monocytes are, therefore, attracted into the central nervous system (CNS), where they change into blood-born microglia and participate in the attempt of removing toxic Aß species. The translocator protein-18 kDa (TSPO) is a transmembrane protein overexpressed in response to neuroinflammation and known to regulate human monocyte chemotaxis. OBJECTIVE: We aimed to evaluate the role of the oligomeric Aß1-42 isoform at inducing peripheral monocyte chemotaxis, and the possible involvement of TSPO in this process. METHODS: In vitro cell lines, and ex vivo monocytes from consecutive AD patients (n = 60), and comparable cognitively intact controls (n = 30) were used. Chemotaxis analyses were carried out through both µ-slide chambers and Boyden assays, using 125 pM oligomeric Aß1-42 as chemoattractant. TSPO agonists and antagonists were tested (Ro5-4864, Emapunil, PK11195). RESULTS: Oligomeric Aß directly promoted chemotaxis in all our models. Interestingly, AD monocytes displayed a stronger response (about twofold) with respect to controls. Aß-induced chemotaxis was prevented by the TSPO antagonist PK11195; the expression of the TSPO and of the C-C chemokine receptor type 2 (CCR2) was unchanged by drug exposure. CONCLUSION: Oligomeric Aß1-42 is able to recruit peripheral monocytes, and we provide initial evidence sustaining a role for TSPO in modulating this process. This data may be of value for future therapeutic interventions aimed at modulating monocytes motility toward the CNS.

Administration of amyloid-ß oligomer to the buccal ganglia may reduce food intake and cholinergic synaptic responses within the feeding neural circuit in Aplysia kurodai.

Anorexia is a behavioral change caused by functional brain disorders in patients with Alzheimer's disease (AD). Amyloid-ß (1-42) oligomers (o-Aß) are possible causative agents of AD that impair signaling via synaptic dysfunction. In this study, we used Aplysia kurodai to study functional disorders of the brain through o-Aß. Administration of o-Aß to the buccal ganglia (feeding brain for oral movements) by surgical treatment significantly reduced food intake for at least five days. Furthermore, we explored the effects of o-Aß on the synaptic function in the feeding neural circuit, focusing on a specific inhibitory synaptic response in jaw-closing motor neurons produced by cholinergic buccal multi-action neurons because we recently found that this cholinergic response decreases with aging, which is consistent with the cholinergic hypothesis for aging. Administration of o-Aß to the buccal ganglia significantly reduced the synaptic response within minutes, whereas administration of amyloid-ß (1-42) monomers did not. These results suggest that o-Aß may impair the cholinergic synapses, even in Aplysia, which is consistent with the cholinergic hypothesis for AD.

A Systematic Review of the Effects of Capsaicin on Alzheimer's Disease.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterised by cognitive impairment, and amyloid-ß plaques and neurofibrillary tau tangles at neuropathology. Capsaicin is a spicy-tasting compound found in chili peppers, with anti-inflammatory, antioxidant, and possible neuroprotective properties. Capsaicin intake has been associated with greater cognitive function in humans, and attenuating aberrant tau hyperphosphorylation in a rat model of AD. This systematic review discusses the potential of capsaicin in improving AD pathology and symptoms. A systematic analysis was conducted on the effect of capsaicin on AD-associated molecular changes, cognitive and behaviour resulting in 11 studies employing rodents and/or cell cultures, which were appraised with the Cochrane Risk of Bias tool. Ten studies showed capsaicin attenuated tau deposition, apoptosis, and synaptic dysfunction; was only weakly effective on oxidative stress; and had conflicting effects on amyloid processing. Eight studies demonstrated improved spatial and working memory, learning, and emotional behaviours in rodents following capsaicin treatment. Overall, capsaicin showed promise in improving AD-associated molecular, cognitive, and behavioural changes in cellular and animal models, and further investigations are recommended to test the readily available bioactive, capsaicin, to treat AD.

Cholesterol, Amyloid Beta, Fructose, and LPS Influence ROS and ATP Concentrations and the Phagocytic Capacity of HMC3 Human Microglia Cell Line.

Research has found that genes specific to microglia are among the strongest risk factors for Alzheimer's disease (AD) and that microglia are critically involved in the etiology of AD. Thus, microglia are an important therapeutic target for novel approaches to the treatment of AD. High-throughput in vitro models to screen molecules for their effectiveness in reversing the pathogenic, pro-inflammatory microglia phenotype are needed. In this study, we used a multi-stimulant approach to test the usefulness of the human microglia cell 3 (HMC3) cell line, immortalized from a human fetal brain-derived primary microglia culture, in duplicating critical aspects of the dysfunctional microglia phenotype. HMC3 microglia were treated with cholesterol (Chol), amyloid beta oligomers (AßO), lipopolysaccharide (LPS), and fructose individually and in combination. HMC3 microglia demonstrated changes in morphology consistent with activation when treated with the combination of Chol + AßO + fructose + LPS. Multiple treatments increased the cellular content of Chol and cholesteryl esters (CE), but only the combination treatment of Chol + AßO + fructose + LPS increased mitochondrial Chol content. Microglia treated with combinations containing Chol + AßO had lower apolipoprotein E (ApoE) secretion, with the combination of Chol + AßO + fructose + LPS having the strongest effect. Combination treatment with Chol + AßO + fructose + LPS also induced APOE and TNF-α expression, reduced ATP production, increased reactive oxygen species (ROS) concentration, and reduced phagocytosis events. These findings suggest that HMC3 microglia treated with the combination of Chol + AßO + fructose + LPS may be a useful high-throughput screening model amenable to testing on 96-well plates to test potential therapeutics to improve microglial function in the context of AD.

Imbalance of multiple neurotransmitter pathways leading to depression-like behavior and cognitive dysfunction in the triple transgenic mouse model of Alzheimer disease.

Depression is among the most frequent psychiatric comorbid conditions in Alzheimer disease (AD). However, pharmacotherapy for depressive disorders in AD is still a big challenge, and the data on the efffcacy of current antidepressants used clinically for depressive symptoms in patients with AD remain inconclusive. Here we investigated the mechanism of the interactions between depression and AD, which we believe would aid in the development of pharmacological therapeutics for the comorbidity of depression and AD. Female APP/PS1/Tau triple transgenic (3×Tg-AD) mice at 24 months of age and age- and sex-matched wild-type (WT) mice were used. The shuttle-box passive avoidance test (PAT) were implemented to assess the abilities of learning and memory, and the open field test (OFT) and the tail suspension test (TST) were used to assess depression-like behavior. High-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was used to detect the level of neurotransmitters related to depression in the hippocampus of mice. The data was identified by orthogonal projections to latent structures discriminant analysis (OPLS-DA). Most neurotransmitters exert their effects by binding to the corresponding receptor, so the expression of relative receptors in the hippocampus of mice was detected using Western blot. Compared to WT mice, 3×Tg-AD mice displayed significant cognitive impairment in the PAT and depression-like behavior in the OFT and TST. They also showed significant decreases in the levels of L-tyrosine, norepinephrine, vanillylmandelic acid, 5-hydroxytryptamine, and acetylcholine, in contrast to significant increases in 5-hydroxyindoleacetic acid, L-histidine, L-glutamine, and L-arginine in the hippocampus. Moreover, the expression of the alpha 1a adrenergic receptor (ADRA1A), serotonin 1 A receptor (5HT1A), and γ-aminobutyric acid A receptor subunit alpha-2 (GABRA2) was significantly downregulated in the hippocampus of 3×Tg-AD mice, while histamine H3 receptor (H3R) expression was significantly upregulated. In addition, the ratio of phosphorylated cAMP-response element-binding protein (pCREB) and CREB was significantly decreased in the hippocampus of 3×Tg-AD mice than WT mice. We demonstrated in the present study that aged female 3×Tg-AD mice showed depression-like behavior accompanied with cognitive dysfunction. The complex and diverse mechanism appears not only relevant to the imbalance of multiple neurotransmitter pathways, including the transmitters and receptors of the monoaminergic, GABAergic, histaminergic, and cholinergic systems, but also related to the changes in L-arginine and CREB signaling molecules.

Methylprednisolone alleviates cognitive functions through the regulation of neuroinflammation in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and linked to abnormal deposition of amyloid-ß (Aß), neurofibrillary tangles (NFTs), synaptic dysfunction, and neuroinflammation. Despite significant progress in unravelling the pathogenesis of AD, currently main therapeutic interventions is limited to symptomatic alleviation. Methylprednisolone (MP), a synthetic glucocorticoid, is recognized for its extensive anti-inflammatory properties. Our study assessed the neuroprotective effect of MP (25 mg/kg) administration to an Aß1-42-induced AD mouse model. Our findings demonstrate that MP treatment can ameliorate cognitive impairment in Aß1-42-induced AD mice and suppress microglial activation in the cortex and hippocampus. RNA-Sequencing analysis reveals that MP ultimately rescues cognitive dysfunction through improving the synapse function and inhibiting the immune and inflammatory processes. Our study suggests that MP could be a promising drug alternative for the treatment of AD, either alone or in combination with other existing drugs.

Taxifolin for Cognitive Preservation in Patients with Mild Cognitive Impairment or Mild Dementia.

BACKGROUND: The development of numerous disease-modifying drugs for age-related dementia has been attempted based on the amyloid-ß (Aß) hypothesis without much success. Taxifolin (TAX), a natural bioactive flavonoid, shows pleiotropic neuroprotective effects with inhibition of Aß aggregation, production, and glycation, antiinflammatory effects, and amelioration of the waste clearance system. We hypothesized that TAX intake is associated with the suppression of cognitive deterioration. OBJECTIVE: To investigate associations between TAX intake and cognitive changes. METHODS: We retrospectively identified patients who orally took TAX 300 mg/day and regularly underwent Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog) and Montreal Cognitive Assessment (MoCA) and compared the temporal changes in ADAS-Cog and MoCA between the non-treatment (pre-TAX) period (180±100 days) and following treatment (on-TAX) period (180±100 days) from June 2020 to November 2021. Since some additional patients underwent the Mini-Mental State Examination (MMSE) instead of the MoCA at the beginning of the pre-TAX period, the same comparison was performed using the MoCA total score converted from MMSE as a sensitivity analysis. RESULTS: Sixteen patients were identified. TAX intake was associated with significantly higher interval changes in the MoCA subscale scores of visuospatial/executive function (p = 0.016), verbal fluency (p = 0.02), and the total score (p = 0.034), but not with ADAS-Cog (total score, p = 0.27). In the sensitivity analysis, 29 patients were included. TAX intake was associated with a significantly higher interval change in the total MoCA score (p = 0.004) but not with ADAS-Cog (p = 0.41). CONCLUSION: Our findings provide a basis for TAX as a novel strategy for maintaining brain health during aging. A prospective cohort study is required to confirm these findings.

Study on the Role of an Erythrocyte Membrane-Coated Nanotheranostic System in Targeted Immune Regulation of Alzheimer's Disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in the elderly population. Despite significant advances in studies of the pathobiology on AD, there is still no effective treatment. Here, an erythrocyte membrane-camouflaged nanodrug delivery system (TR-ZRA) modified with transferrin receptor aptamers that can be targeted across the blood-brain barrier to ameliorate AD immune environment is established. Based on metal-organic framework (Zn-CA), TR-ZRA is loaded with CD22shRNA plasmid to silence the abnormally high expression molecule CD22 in aging microglia. Most importantly, TR-ZRA can enhance the ability of microglia to phagocytose Aß and alleviate complement activation, which can promote neuronal activity and decrease inflammation level in the AD brain. Moreover, TR-ZRA is also loaded with Aß aptamers, which allow rapid and low-cost monitoring of Aß plaques in vitro. After treatment with TR-ZRA, learning, and memory abilities are enhanced in AD mice. In conclusion, the biomimetic delivery nanosystem TR-ZRA in this study provides a promising strategy and novel immune targets for AD therapy.