Structural identification and anti-neuroinflammatory effect of a heteropolysaccharide ATP50-3 from Acorus tatarinowii rhizome.

Acorus tatarinowii, a famous traditional Chinese medicine, is used for the clinical treatment of memory impairment and dementia. In this research, AT50, the crude polysaccharide extracted from A. tatarinowii rhizome, significantly improved the memory and learning ability of mice with Alzheimer's disease (AD) and exerted excellent anti-neuroinflammatory effects. More importantly, AT50 returned the levels of NO, TNF-α, IL-1ß, PGE-2, and IL-6 in AD mouse brains to normal levels. To identify the active ingredients in AT50, a heteropolysaccharide ATP50-3 was obtained from AT50. Structural analysis indicated ATP50-3 consisted of α-L-Araf-(1→, →2)-α-L-Araf-(1→, →3)-α-L-Araf-(1→, →5)-α-L-Araf-(1→, α-D-Xylp-(1→, →3,4)-ß-D-Xylp-(1→, →3)-α-D-Galp-(1→, →3,6)-α-D-Galp-(1→, →6)-4-OAc-α-D-Galp-(1→, →3,4,6)-α-D-Galp-(1→, →4)-α-D-Glcp-(1→, →2,3,6)-ß-D-Glcp-(1→, →4,6)-α-D-Manp-(1→, →3,4)-α-L-Rhap-(1→, →4)-α-D-GalpA-(1→, and →4)-α-D-GlcpA-(1 â†’ residues and terminated with Xyl and Ara. Additionally, ATP50-3 significantly inhibited the release of proinflammatory factors in lipopolysaccharide-stimulated BV2 cells. ATP50-3 may be an active constituent of AT50, responsible for its anti-neuroinflammatory effects, with great potential to treat AD.

Memory circuits in dementia: The engram, hippocampal neurogenesis and Alzheimer's disease.

Here, we provide an in-depth consideration of our current understanding of engrams, spanning from molecular to network levels, and hippocampal neurogenesis, in health and Alzheimer's disease (AD). This review highlights novel findings in these emerging research fields and future research directions for novel therapeutic avenues for memory failure in dementia. Engrams, memory in AD, and hippocampal neurogenesis have each been extensively studied. The integration of these topics, however, has been relatively less deliberated, and is the focus of this review. We primarily focus on the dentate gyrus (DG) of the hippocampus, which is a key area of episodic memory formation. Episodic memory is significantly impaired in AD, and is also the site of adult hippocampal neurogenesis. Advancements in technology, especially opto- and chemogenetics, have made sophisticated manipulations of engram cells possible. Furthermore, innovative methods have emerged for monitoring neurons, even specific neuronal populations, in vivo while animals engage in tasks, such as calcium imaging. In vivo calcium imaging contributes to a more comprehensive understanding of engram cells. Critically, studies of the engram in the DG using these technologies have shown the important contribution of hippocampal neurogenesis for memory in both health and AD. Together, the discussion of these topics provides a holistic perspective that motivates questions for future research.

Visual analysis on the study status and trends of acupuncture and moxibustion for Alzheimer's disease. / é’ˆç¸æ²»ç–—é˜¿å°”èŒ¨æµ·é»˜ç— ç ”ç©¶çŠ¶å†µåŠè¶‹åŠ¿çš„å¯è§†åŒ–åˆ†æž.

The research history, hot spots and frontier trends of acupuncture and moxibustion for Alzheimer's disease (AD) were explored using knowledge graph technology. The articles on acupuncture and moxibustion for AD were searched from 6 databases, i.e. CNKI, VIP, Wanfang, SinoMed, Pubmed and Web of Science, from January 1st, 1993 to January 1st, 2023. Using CiteSpace6.2.R2 Advance and VOSviewer V1.6.19 softwares, the knowledge map was graphed and the visual analysis was performed. A total of 1 228 Chinese and 309 English articles were included. The high-frequency keywords were generally divided into the keywords of clinical diseases (AD, dementia), those of therapeutic methods (electroacupuncture, acupuncture-moxibustion and acupuncture) and those of mechanism study (ß-amyloid, mice). Thirteen keyword clusters were formed among the articles of Chinese version, e.g. acupuncture-moxibustion, dementia, acupuncture and electroacupuncture; and 8 clusters were obtained among English articles, e.g. electroacupuncture, drug therapy and hippocampus. The high-frequency keywords of acupoints included Baihui (GV 20), Dazhui (GV 14), Yintang (GV 24+), Zusanli (ST 36), Fenglong (ST 40), etc. Six clusters of "acupuncture techniques → acupoints" were obtained for the treatment of AD with acupuncture and moxibustion. The therapeutic methods and modes of AD with acupuncture and moxibustion are constantly progressed, the development of clinical research tends to the evaluation of novel therapeutic mode and clinical effect, and the mechanism of acupuncture and moxibustion for the effect on AD are more deeply explored. Among the various therapeutic methods, acupuncture-moxibustion, acupuncture and electroacupuncture have been early predominant; while, many novel methods are gradually displayed later, such as music electroacupuncture and hydro-acupuncture. In recent 30 years, among Chinese and English articles for the studies of AD treated with acupuncture and moxibustion, the theme of them focuses on the two aspects, the observation of clinical effect and the mechanism research. It is found that the clinical therapeutic methods have been gradually improved and the mechanism exploration been deepened.

[Role of NLRP3 inflammasome in prevention and treatment of cognitive impairment-related diseases and traditional Chinese medicine intervention: a review].

Alzheimer's disease(AD), vascular dementia(VD), and traumatic brain injury(TBI) are more common cognitive impairment diseases characterized by high disability and mortality rates, imposing a heavy burden on individuals and their families. Although AD, VD, and TBI have different specific mechanisms, their pathogenesis is closely related to the nucleotide-binding oligome-rization domain-like receptor protein 3(NLRP3). The NLRP3 inflammasome is involved in neuroinflammatory responses, mediating microglial polarization, regulating the reduction of amyloid ß-protein(Aß) deposition, neurofibrillary tangles(NFTs) formation, autophagy regulation, and maintaining brain homeostasis, and synaptic stability, thereby contributing to the development of AD, VD, and TBI. Previous studies have shown that traditional Chinese medicine(TCM) can alleviate neuroinflammation, promote microglial polarization towards the M2 phenotype, reduce Aß deposition and NFTs formation, regulate autophagy, and maintain brain homeostasis by intervening in NLRP3 inflammasome, hence exerting a role in preventing and treating cognitive impairment-related diseases, reducing psychological and economic pressure on patients, and improving their quality of life. Therefore, this article elucidated the role of NLRP3 inflammasome in AD, VS, and TBI, and provided a detailed summary of the latest research results on TCM intervention in NLRP3 inflammasome for the prevention and treatment of these diseases, aiming to inherit the essence of TCM and provide references and foundations for clinical prevention and treatment of cognitive impairment-related diseases with TCM. Meanwhile, this also offers insights and directions for further research in TCM for the prevention and treatment of cognitive impairment-related diseases.

Inhibition of polyphenols on Maillard reaction products and their induction of related diseases: A comprehensive review.

BACKGROUND: Food products undergo a pronounced Maillard reaction (MR) during the cooking process, leading to the generation of substantial quantities of Maillard reaction products (MRPs). Within this category, advanced glycation end products (AGEs), acrylamide (AA), and heterocyclic amines (HAs) have been implicated as potential risk factors associated with the development of diseases. PURPOSE: To explore the effects of polyphenols, a class of bioactive compounds found in plants, on the inhibition of MRPs and related diseases. Previous research has mainly focused on their interactions with proteins and their effects on the gastrointestinal tract and other diseases, while fewer studies have examined their inhibitory effects on MRPs. The aim is to offer a scientific reference for future research investigating the inhibitory role of polyphenols in the MR. METHODS: The databases PubMed, Embase, Web of Science and The Cochrane Library were searched for appropriate research. RESULTS: Polyphenols have the potential to inhibit the formation of harmful MRPs and prevent related diseases. The inhibition of MRPs by polyphenols primarily occurs through the following mechanisms: trapping α-dicarbonyl compounds, scavenging free radicals, chelating metal ions, and preserving protein structure. Simultaneously, polyphenols exhibit the ability to impede the onset and progression of related diseases such as diabetes, atherosclerosis, cancer, and Alzheimer's disease through diverse pathways. CONCLUSION: This review presents that inhibition of polyphenols on Maillard reaction products and their induction of related diseases. Further research is imperative to enhance our comprehension of additional pathways affected by polyphenols and to fully uncover their potential application value in inhibiting MRPs.

Lycium Barbarum Polysaccharides Improves Cognitive Functions in ICV-STZ-Induced Alzheimer's Disease Mice Model by Improving the Synaptic Structural Plasticity and Regulating IRS1/PI3K/AKT Signaling Pathway.

Lycium barbarum polysaccharide (LBP) have a certain curative effect on hypoglycemic and neuroprotective effects, but the specific mechanism is unclear and needs to be further explored. This study aimed to clarify the mechanisms of LBP in the treatment of ICV-STZ mice model of AD from the perspectives of insulin resistance, IRS1/PI3K/AKT signaling pathway, and synaptic protein expression. We used male C57BL/6J mice injected with STZ (3 mg/kg) in the lateral ventricle as an AD model. After treatment with LBP, the learning and memory abilities of ICV-STZ mice were enhanced, and the pathological changes in brain tissue were alleviated. LBP can regulate the expression of proteins related to the IRS1/PI3K/AKT signaling pathway and thereby reducing Aß deposition and tau protein phosphorylation in the brain of ICV-STZ mice. In addition, LBP also can up-regulate the expression of synaptic proteins. The results indicated that LBP played a neuroprotective role by regulating the IRS1/PI3K/AKT pathway, inhibiting tau protein hyperphosphorylation and improving the expression levels of synapse-related proteins.

Exploring Acori Tatarinowii Rhizoma and Polygalae Radix in Alzheimer's: Network pharmacology and molecular docking analysis.

Explore Acori Tatarinowii Rhizoma (ATR) and Polygalae Radix (PR) mechanisms in Alzheimer's disease (AD) treatment through network pharmacology. ATR-PR was investigated in the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, Batman, and Traditional Chinese Medicines Integrated Database (TCMID) to gather information on its chemical components and target proteins. Target genes associated with AD were retrieved from the GeneCards and National Center for Biotechnology Information (NCBI) databases. The integration of these datasets with potential targets facilitated the construction of an AD and ATR-PR protein-protein interaction (PPI) network using the STRING database. The resulting network identified the core active ingredients and main targets of ATR-PR in AD treatment. Cluster analysis of the PPI network was performed using Cytoscape 3.7.1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted using the Metascape database. Molecular docking simulations revealed potential interactions between the main active ingredients and core targets. Our analysis identified 8 putative components and 455 targets of ATR-PR. We systematically searched for 1306 genes associated with AD, conducted Venn diagram analysis resulting in 156 common targets, and constructed a PPI network with 57 key targets. GO functional analysis highlighted the primary biological processes associated with oxidative stress. KEGG pathway enrichment analysis revealed the involvement of 64 signaling pathways, with the PI3K/Akt signaling pathway playing a key role. Molecular docking analysis indicated a high affinity between the potential targets of ATR-PR and the main compounds of AD. This study sheds light on the complex network of interactions involving ATR-PR in the context of AD. The identified targets, pathways, and interactions provide a foundation for understanding the potential therapeutic mechanisms. The involvement of oxidative stress-related processes and the crucial role of the PI3K/Akt signaling pathway suggest avenues for targeted therapeutic interventions in Alzheimer's disease treatment. Our proposition of the combined use of ATR-PR has emerged as a potential treatment strategy for AD, supported by a network pharmacology approach. This framework provides a robust foundation for future clinical applications and experimental research in the pursuit of effective Alzheimer's disease treatments.

Network Pharmacology and Molecular Docking Identify the Potential Mechanism and Therapeutic Role of Scutellaria baicalensis in Alzheimer's Disease.

Aim: Scutellaria baicalensis, a traditional Chinese medicinal herb renowned for its anti-inflammatory, antioxidant, and anti-tumor properties, has shown promise in alleviating cognitive impairment associated with Alzheimer's disease. Nonetheless, the exact neuroprotective mechanism of Scutellaria baicalensis against Alzheimer's disease remains unclear. In this study, network pharmacology was employed to explore the possible mechanisms by which Scutellaria baicalensis protects against Alzheimer's disease. Methods: The active compounds of Scutellaria baicalensis were retrieved from the TCMSP database, and their corresponding targets were identified. Alzheimer's disease-related targets were obtained through searches in the GeneCards and OMIM databases. Cytoscape 3.6.0 software was utilized to construct a regulatory network illustrating the "active ingredient-target" relationships. Subsequently, the target genes affected by Scutellaria baicalensis in the context of Alzheimer's disease were input into the String database to establish a PPI network. GO analysis and KEGG analysis were conducted using the DAVID database to predict the potential pathways associated with these key targets. Following this, the capacity of these active ingredients to bind to core targets was confirmed through molecular docking. In vitro experiments were then carried out for further validation. Results: A total of 36 active ingredients from Scutellaria baicalensis were screened out, which corresponded to 365 targets. Molecular docking results demonstrated the robust binding abilities of Baicalein, Wogonin, and 5,2'-Dihydroxy-6,7,8-trimethoxyflavone to key target proteins (SRC, PIK3R1, and STAT3). In vitro experiments showed that the active components of Scutellaria baicalensis can inhibit STAT3 expression by downregulating the PIK3R1/SRC pathway in Neuro 2A cells. Conclusion: In summary, these findings collectively suggest that Scutellaria baicalensis holds promise as a viable treatment option for Alzheimer's disease.

Mulberry Leaf Compounds and Gut Microbiota in Alzheimer's Disease and Diabetes: A Study Using Network Pharmacology, Molecular Dynamics Simulation, and Cellular Assays.

Recently, studies have reported a correlation that individuals with diabetes show an increased risk of developing Alzheimer's disease (AD). Mulberry leaves, serving as both a traditional medicinal herb and a food source, exhibit significant hypoglycemic and antioxidative properties. The flavonoid compounds in mulberry leaf offer therapeutic effects for relieving diabetic symptoms and providing neuroprotection. However, the mechanisms of this effect have not been fully elucidated. This investigation aimed to investigate the combined effects of specific mulberry leaf flavonoids (kaempferol, quercetin, rhamnocitrin, tetramethoxyluteolin, and norartocarpetin) on both type 2 diabetes mellitus (T2DM) and AD. Additionally, the role of the gut microbiota in these two diseases' treatment was studied. Using network pharmacology, we investigated the potential mechanisms of flavonoids in mulberry leaves, combined with gut microbiota, in combating AD and T2DM. In addition, we identified protein tyrosine phosphatase 1B (PTP1B) as a key target for kaempferol in these two diseases. Molecular docking and molecular dynamics simulations showed that kaempferol has the potential to inhibit PTP1B for indirect treatment of AD, which was proven by measuring the IC50 of kaempferol (279.23 µM). The cell experiment also confirmed the dose-dependent effect of kaempferol on the phosphorylation of total cellular protein in HepG2 cells. This research supports the concept of food-medicine homology and broadens the range of medical treatments for diabetes and AD, highlighting the prospect of integrating traditional herbal remedies with modern medical research.

Supplements for cognitive ability in patients with mild cognitive impairment or Alzheimer's disease: a protocol for systematic review and network meta-analysis of randomised controlled trials.

INTRODUCTION: Considering the increasing incidence of Alzheimer's disease (AD) and mild cognitive impairment (MCI) worldwide, there is an urgent need to identify efficacious, safe and convenient treatments. Numerous investigations have been conducted on the use of supplements in this domain, with oral supplementation emerging as a viable therapeutic approach for AD or MCI. Nevertheless, given the multitude of available supplements, it becomes imperative to identify the optimal treatment regimen. METHODS AND ANALYSIS: Eight academic databases and three clinical trial registries will be searched from their inception to 1 June 2023. To identify randomised controlled trials investigating the effects of supplements on patients with AD or MCI, two independent reviewers (X-YZ and Y-QL) will extract relevant information from eligible articles, while the risk of bias in the included studies will be assessed using the Rob 2.0 tool developed by the Cochrane Collaboration. The primary outcome of interest is the overall cognitive function. Pair-wise meta-analysis will be conducted using RevMan V.5.3, while network meta-analysis will be carried out using Stata 17.0 and ADDIS 1.16.8. Heterogeneity test, data synthesis and subgroup analysis will be performed if necessary. The GRADE system will be employed to assess the quality of evidence. This study is scheduled to commence on 1 June 2023 and conclude on 1 October 2023. ETHICS AND DISSEMINATION: Ethics approval is not required for systematic review and network meta-analysis. The results will be submitted to a peer-reviewed journal or at a conference. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42023414700).

Anorexigenic neuropeptides as anti-obesity and neuroprotective agents: exploring the neuroprotective effects of anorexigenic neuropeptides.

Since 1975, the incidence of obesity has increased to epidemic proportions, and the number of patients with obesity has quadrupled. Obesity is a major risk factor for developing other serious diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular diseases. Recent epidemiologic studies have defined obesity as a risk factor for the development of neurodegenerative diseases, such as Alzheimer's disease (AD) and other types of dementia. Despite all these serious comorbidities associated with obesity, there is still a lack of effective antiobesity treatment. Promising candidates for the treatment of obesity are anorexigenic neuropeptides, which are peptides produced by neurons in brain areas implicated in food intake regulation, such as the hypothalamus or the brainstem. These peptides efficiently reduce food intake and body weight. Moreover, because of the proven interconnection between obesity and the risk of developing AD, the potential neuroprotective effects of these two agents in animal models of neurodegeneration have been examined. The objective of this review was to explore anorexigenic neuropeptides produced and acting within the brain, emphasizing their potential not only for the treatment of obesity but also for the treatment of neurodegenerative disorders.

Nature's Toolbox for Alzheimer's Disease: A Review on the Potential of Natural Products as Alzheimer's Disease Drugs.

Numerous clinical trials involving natural products have been conducted to observe cognitive performances and biomarkers in Alzheimer's Disease (AD) patients. However, to date, no natural-based drugs have been approved by the FDA as treatments for AD. In this review, natural product-based compounds that were tested in clinical trials from 2011 to 2023, registered at www.clinicaltrials.gov were reviewed. Thirteen compounds, encompassing 7 different mechanisms of action were covered. Several observations were deduced, which are: i) several compounds showed cognitive improvement, but these improvements may not extend to AD, ii) compounds that are endogenous to the human body showed better outcomes, and iii) Docosahexaenoic acid (DHA) and cerebrolysin had the most potential as AD drugs among the 13 compounds. Based on the current findings, natural products may be more suitable as a supplement than AD drugs in most cases. However, the studies covered here were conducted in a relatively short amount of time, where compounds acting on AD pathways may take time to show any effect. Given the diverse pathways that these natural products are involved in, they may potentially produce synergistic effects that would be beneficial in treating AD. Additionally, natural products benefit from both physicochemical properties being in more favorable ranges and active transport playing a more significant role than it does for synthetic compounds.

Repurposing non-pharmacological interventions for Alzheimer's disease through link prediction on biomedical literature.

Non-pharmaceutical interventions (NPI) have great potential to improve cognitive function but limited investigation to discover NPI repurposing for Alzheimer's Disease (AD). This is the first study to develop an innovative framework to extract and represent NPI information from biomedical literature in a knowledge graph (KG), and train link prediction models to repurpose novel NPIs for AD prevention. We constructed a comprehensive KG, called ADInt, by extracting NPI information from biomedical literature. We used the previously-created SuppKG and NPI lexicon to identify NPI entities. Four KG embedding models (i.e., TransE, RotatE, DistMult and ComplEX) and two novel graph convolutional network models (i.e., R-GCN and CompGCN) were trained and compared to learn the representation of ADInt. Models were evaluated and compared on two test sets (time slice and clinical trial ground truth) and the best performing model was used to predict novel NPIs for AD. Discovery patterns were applied to generate mechanistic pathways for high scoring candidates. The ADInt has 162,212 nodes and 1,017,284 edges. R-GCN performed best in time slice (MR = 5.2054, Hits@10 = 0.8496) and clinical trial ground truth (MR = 3.4996, Hits@10 = 0.9192) test sets. After evaluation by domain experts, 10 novel dietary supplements and 10 complementary and integrative health were proposed from the score table calculated by R-GCN. Among proposed novel NPIs, we found plausible mechanistic pathways for photodynamic therapy and Choerospondias axillaris to prevent AD, and validated psychotherapy and manual therapy techniques using real-world data analysis. The proposed framework shows potential for discovering new NPIs for AD prevention and understanding their mechanistic pathways.

Gegen Qinlian tablets delay Alzheimer's disease progression via inhibiting glial neuroinflammation and remodeling gut microbiota homeostasis.

BACKGROUND: Current therapeutic agents for AD have limited efficacy and often induce undesirable side effects. Gegen Qinlian tablets (GGQLT) are a well-known clearingheat formula used in clinical treatment of inflammatory diseases. Based on traditional Chinese medicine (TCM) theory, the strategy of clearing-heat is then compatible with the treatment of AD. However, it remains unknown whether GGQLT can exert neuroprotective effects and alleviate neuroinflammation in AD. PURPOSE: This study aimed to evaluate the anti-AD effects of GGQLT and to decipher its intricate mechanism using integrative analyses of network pharmacology, transcriptomic RNA sequencing, and gut microbiota. METHODS: The ingredients of GGQLT were analyzed using HPLC-ESI-Q/TOF-MS. The AD model was established by bilateral injection of Aß1-42 into the intracerebroventricular space of rats. The Morris water maze was used to evaluate the cognitive function of the AD rats. The long-term toxicity of GGQLT in rats was assessed by monitoring their body weights and pathological alterations in the liver and kidney. Reactive astrocytes and microglia were assessed by immunohistochemistry by labeling GFAP and Iba-1. The levels of inflammatory cytokines in the hippocampus were evaluated using ELISA kits, RT-PCR, and Western blot, respectively. The potential anti-AD mechanism was predicted by analyses of RNA-sequencing and network pharmacology. Western blot and immunohistochemistry were utilized to detect the phosphorylation levels of IκBα, NF-κB p65, p38, ERK and JNK. The richness and composition of gut bacterial and fungal microflora were investigated via 16S rRNA and ITS sequencing. RESULTS: Typical ingredients of GGQLT were identified using HPLC-ESI-Q/TOF-MS. GGQLT significantly improved the cognitive function of AD rats by suppressing the activation of microglia and astrocytes, improving glial morphology, and reducing the neuroinflammatory reactions in the hippocampus. RNA-sequencing, network and experimental pharmacological studies demonstrated that GGQLT inhibited the activation of NF-κB/MAPK signaling pathways in the hippocampus. GGQLT could also restore abnormal gut bacterial and fungal homeostasis and no longer-term toxicity of GGQLT was observed. CONCLUSIONS: Our findings, for the first time, demonstrate GGQLT exhibit anti-AD effects and is worthy of further exploration and development.

In Vitro and In Vivo Insights into a Broccoli Byproduct as a Healthy Ingredient for the Management of Alzheimer's Disease and Aging through Redox Biology.

Broccoli has gained popularity as a highly consumed vegetable due to its nutritional and health properties. This study aimed to evaluate the composition profile and the antioxidant capacity of a hydrophilic extract derived from broccoli byproducts, as well as its influence on redox biology, Alzheimer's disease markers, and aging in the Caenorhabditis elegans model. The presence of glucosinolate was observed and antioxidant capacity was demonstrated both in vitro and in vivo. The in vitro acetylcholinesterase inhibitory capacity was quantified, and the treatment ameliorated the amyloid-ß- and tau-induced proteotoxicity in transgenic strains via SOD-3 and SKN-1, respectively, and HSP-16.2 for both parameters. Furthermore, a preliminary study on aging indicated that the extract effectively reduced reactive oxygen species levels in aged worms and extended their lifespan. Utilizing broccoli byproducts for nutraceutical or functional foods could manage vegetable processing waste, enhancing productivity and sustainability while providing significant health benefits.

Biochemical and Biophysical Characterization of Tau and α-Linolenic Acid Vesicles In Vitro.

Alzheimer's disease (AD) is characterized by the abnormal accumulation of disordered protein, that is, extracellular senile plaques of amyloid-ß (Aß) and intracellular neurofibrillary tangles of Tau. Tau protein has gained the attention in recent years owing to the ability to propagate in a "prion-like" nature. The disordered protein Tau possesses a high positive charge, which allows its binding to anionic proteins and factors. The native disorder of proteins attends the ß-sheet structure from its random-coiled conformation upon charge compensation by various polyanionic agents such as heparin, RNA, etc. Anionic lipids such as arachidonic acid (AA) and oleic acid (OA) are also one of the factors which can induce aggregation of Tau in physiological conditions. The free units of Tau protein can bind to lipid membranes through its repeat domain (RD), the anionic side chains of the membrane lipids induce aggregation of Tau by reducing the activation barrier. In this study, we investigated the role of α-linolenic acid (ALA) as an inducing agent for Tau aggregation in vitro conditions. Omega-3 fatty acids bear a capacity to reduce the pathology of Tau by downregulating the Tau phosphorylation pathway. We have studied by using various biochemical or biophysical methods the potency of ALA as an aggregating agent for Tau. We have implemented different techniques such as SDS-PAGE, transmission electron microscopy, CD spectroscopy to evaluated higher-order aggregates of Tau upon induction by ALA.

α-Linolenic Acid Induces Microglial Activation and Extracellular Tau Internalization.

Neuroinflammation is the brain condition that occurs due to the hyper-activation of brain's immune cells and microglia, over the stimulation of extracellular aggregated proteins such as amyloid plaques and by extracellular Tau as well. The phenotypic changes of microglia from inflammatory to anti-inflammatory can be triggered by many factors, which also includes dietary fatty acids. The classes of omega-3 fatty acids are the majorly responsible in maintaining the anti-inflammatory phenotype of microglia. The enhanced phagocytic ability of microglia might induce the clearance of extracellular aggregated proteins, such as amyloid beta and Tau. In this study, we emphasized on the effect of α-linolenic acid (ALA) on the activation of microglia and internalization of the extracellular Tau seed in microglia.

Phytochemicals targeting Alzheimer's disease via the AMP-activated protein kinase pathway, effects, and mechanisms of action.

Alzheimer's disease (AD), characterized by cognitive dysfunction and other behavioral abnormalities, is a progressive neurodegenerative disease that occurs due to aging. Currently, effective drugs to mitigate or treat AD remain unavailable. AD is associated with several abnormalities in neuronal energy metabolism, such as decreased glucose uptake, mitochondrial dysfunction, and defects in cholesterol metabolism. Amp-activated protein kinase (AMPK) is an important serine/threonine protein kinase that regulates the energy status of cells. AMPK is widely present in eukaryotic cells and can sense and regulate energy metabolism to maintain energy supply and demand balance, making it a promising target for energy metabolism-based AD therapy. Therefore, this review aimed to discuss the molecular mechanism of AMPK in the pathogenesis of AD to provide a theoretical basis for the development of new anti-AD drugs. To review the mechanisms of phytochemicals in the treatment of AD via AMPK pathway regulation, we searched PubMed, Google Scholar, Web of Science, and Embase databases using specific keywords related to AD and phytochemicals in September 2023. Phytochemicals can activate AMPK or regulate the AMPK pathway to exert therapeutic effects in AD. The anti-AD mechanisms of these phytochemicals include inhibiting Aß aggregation, preventing Tau hyperphosphorylation, inhibiting inflammatory response and glial activation, promoting autophagy, and suppressing anti-oxidative stress. Additionally, several AMPK-related pathways are involved in the anti-AD mechanism, including the AMPK/CaMKKß/mTOR, AMPK/SIRT1/PGC-1α, AMPK/NF-κB/NLRP3, AMPK/mTOR, and PERK/eIF2α pathways. Notably, urolithin A, artemisinin, justicidin A, berberine, stigmasterol, arctigenin, and rutaecarpine are promising AMPK agonists with anti-AD effects. Several phytochemicals are effective AMPK agonists and may have potential applications in AD treatment. Overall, phytochemical-based drugs may overcome the barriers to the effective treatment of neurodegenerative diseases.

Curcumin and omega-3 polyunsaturated fatty acids as bioactive food components with synergistic effects on Alzheimer's disease.

Curcumin and omega-3 polyunsaturated fatty acids (ω-3 PUFA) are multifunctional compounds which play an important role in Alzheimer's disease (AD) and little has been addressed about the role of these two compounds together in the progression of the disease. There is evidence of the beneficial effect of combined administration of ω-3 PUFA and other dietary supplements such as vitamins and polyphenols in the prevention of AD, although much remains to be understood about their possible complementary or synergistic activity. Therefore, the objective of this work is to review the research focused on studying the effect and mechanisms of action of curcumin, ω-3 PUFA, and the combination of these nutraceutical compounds, particularly on AD, and to integrate the possible ways in which these compounds can potentiate their effect. The most important pathophysiologies that manifest in AD will be addressed, in order to have a better understanding of the mechanisms of action through which these bioactive compounds exert a neuroprotective effect.

Translation from Preclinical Research to Clinical Trials: Brain-Gut Photobiomodulation Therapy for Alzheimer's Disease.

Recently, novel non-pharmacological interventions, such as photobiomodulation (PBM) therapy, have shown promise for the treatment of Alzheimer's disease (AD). This article outlines the translation from the preclinical to clinical stages of an innovative brain-gut PBM therapy in a mouse model of AD, a pilot clinical trial involving mild-to-moderate AD patients, and a continuing pivotal clinical trial with a similar patient population. In a mouse model of AD (Aß25-35), daily application of brain-gut PBM therapy to both the head and the abdomen produced a neuroprotective effect against the neurotoxic effects of an Aß25-35 peptide injection by normalizing all the modified behavioral and biochemical parameters. The pilot clinical trial to evaluate brain-gut PBM therapy demonstrated the tolerability and feasibility of the novel PBM-based treatment for mild-to-moderate AD patients. Compared to the sham patients, the PBM-treated patients had lower Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) comprehension sub-scores, higher forward verbal spans, and lower Trail Making Test (TMT) Part B (TMT-B) execution times, which suggest an improvement in cognitive functions. This pilot study provided important information for the design of a novel pivotal clinical trial, currently in progress, to assess the efficacy of brain-gut PBM therapy in a larger sample of AD patients. This pivotal clinical trial could demonstrate that brain-gut PBM therapy is a safe, well-tolerated, and efficient disease-modifying treatment for mild-to-moderate AD patients and that it has medical and economic benefits.