The Clinical Role of Heart Rate Variability Assessment in Cognitively Impaired Patients and Its Applicability in Community Care Settings: A Systematic Review of the Literature.

Heart rate variability (HRV) correlates well with a person's overall physiological function. Clinically, HRV is successfully used in acute care to identify impending infections, but little is known about its potential in the management of chronic diseases like cognitive decline/dementia. The aim of this study was to identify the best available knowledge about HRV in cognitively impaired populations that might be applied to improve clinical practice in community settings. We conducted a systematic literature search in PubMed, Embase, and Cochrane databases published from January 2009 to August 2022. Eligible studies were selected using Covidence and each study underwent qualitative assessment using the Mixed Method Appraisal Tool. At each stage of selection, each study was reviewed independently by two members of the team, and any disputes were discussed along the way. The literature identified that the brain regions controlling HRV are also those affected by dementias of Alzheimer's type (AD) and Lewy body types (DLB). HRV was impaired in both types, with DLB showing greater impairment in all HRV parameters compared to AD. No studies explored the temporal changes of HRV or its use in the clinical management of people with cognitive impairment (CI). The current lack of standardization of HRV recording and analysis limits its use in clinical practice. HRV may emerge as a potentially useful tool to identify people with early/preclinical memory impairment and help to differentiate AD from DLB. Longitudinal HRV measurement is emerging as a useful way to monitor disease progression and treatment response, and continuous HRV measurement may prove useful in the early identification of sepsis and its complications in patients no longer able to communicate their illness experiences.

Role of Calcitriol and Vitamin D Receptor (VDR) Gene Polymorphisms in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by amyloid beta (Aß) buildup and neuronal degeneration. An association between low serum vitamin D levels and an increased risk of AD has been reported in several epidemiological studies. Calcitriol (1,25-dihydroxycholecalciferol) is the active form of vitamin D, and is generated in the kidney and many other tissues/organs, including the brain. It is a steroid hormone that regulates important functions like calcium/phosphorous levels, bone mineralization, and immunomodulation, indicating its broader systemic significance. In addition, calcitriol confers neuroprotection by mitigating oxidative stress and neuroinflammation, promoting the clearance of Aß, myelin formation, neurogenesis, neurotransmission, and autophagy. The receptors to which calcitriol binds (vitamin D receptors; VDRs) to exert its effects are distributed over many organs and tissues, representing other significant roles of calcitriol beyond sustaining bone health. The biological effects of calcitriol are manifested through genomic (classical) and non-genomic actions through different pathways. The first is a slow genomic effect involving nuclear VDR directly affecting gene transcription. The association of AD with VDR gene polymorphisms relies on the changes in vitamin D consumption, which lowers VDR expression, protein stability, and binding affinity. It leads to the altered expression of genes involved in the neuroprotective effects of calcitriol. This review summarizes the neuroprotective mechanism of calcitriol and the role of VDR polymorphisms in AD, and might help develop potential therapeutic strategies and markers for AD in the future.

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.

Neurotoxic Microglial Activation via IFNγ-Induced Nrf2 Reduction Exacerbating Alzheimer's Disease.

Microglial neuroinflammation appears to be neuroprotective in the early pathological stage, yet neurotoxic, which often precedes neurodegeneration in Alzheimer's disease (AD). However, it remains unclear how the microglial activities transit to the neurotoxic state during AD progression, due to complex neuron-glia interactions. Here, the mechanism of detrimental microgliosis in AD by employing 3D human AD mini-brains, brain tissues of AD patients, and 5XFAD mice is explored. In the human and animal AD models, amyloid-beta (Aß)-overexpressing neurons and reactive astrocytes produce interferon-gamma (IFNγ) and excessive oxidative stress. IFNγ results in the downregulation of mitogen-activated protein kinase (MAPK) and the upregulation of Kelch-like ECH-associated Protein 1 (Keap1) in microglia, which inactivate nuclear factor erythroid-2-related factor 2 (Nrf2) and sensitize microglia to the oxidative stress and induces a proinflammatory microglia via nuclear factor kappa B (NFκB)-axis. The proinflammatory microglia in turn produce neurotoxic nitric oxide and proinflammatory mediators exacerbating synaptic impairment, phosphorylated-tau accumulation, and discernable neuronal loss. Interestingly, recovering Nrf2 in the microglia prevents the activation of proinflammatory microglia and significantly blocks the tauopathy in AD minibrains. Taken together, it is envisioned that IFNγ-driven Nrf2 downregulation in microglia as a key target to ameliorate AD pathology.

Overexpression of MTMR14 induced learning and memory impairments in 2-month-old C57 mice.

Multiple biological functions of MTMR14 including regulation of autophagy, inflammation and Ca2+ homeostasis have been reported. However, its functional contribution to learning and memory remains unclear. In this study, we investigated whether upregulation of MTMR14 induced cognitive impairment and the underlying mechanisms. MTMR14 level was significantly increased in cells or brain tissues that overexpressed P301S-tau. The fusion of autophagosome and lysosome was significantly inhibited by overexpression of MTMR14 or P301S-tau. Upregulation of MTMR14 led to cognitive impairments in 2-month-old mice by inhibiting synaptic protein expression. These findings suggest that MTMR14 may be a key risk factor for cognitive ability.

Network analysis-guided drug repurposing strategies targeting LPAR receptor in the interplay of COVID, Alzheimer's, and diabetes.

The COVID-19 pandemic caused by the SARS-CoV-2 virus has greatly affected global health. Emerging evidence suggests a complex interplay between Alzheimer's disease (AD), diabetes (DM), and COVID-19. Given COVID-19's involvement in the increased risk of other diseases, there is an urgent need to identify novel targets and drugs to combat these interconnected health challenges. Lysophosphatidic acid receptors (LPARs), belonging to the G protein-coupled receptor family, have been implicated in various pathological conditions, including inflammation. In this regard, the study aimed to investigate the involvement of LPARs (specifically LPAR1, 3, 6) in the tri-directional relationship between AD, DM, and COVID-19 through network analysis, as well as explore the therapeutic potential of selected anti-AD, anti-DM drugs as LPAR, SPIKE antagonists. We used the Coremine Medical database to identify genes related to DM, AD, and COVID-19. Furthermore, STRING analysis was used to identify the interacting partners of LPAR1, LPAR3, and LPAR6. Additionally, a literature search revealed 78 drugs on the market or in clinical studies that were used for treating either AD or DM. We carried out docking analysis of these drugs against the LPAR1, LPAR3, and LPAR6. Furthermore, we modeled the LPAR1, LPAR3, and LPAR6 in a complex with the COVID-19 spike protein and performed a docking study of selected drugs with the LPAR-Spike complex. The analysis revealed 177 common genes implicated in AD, DM, and COVID-19. Protein-protein docking analysis demonstrated that LPAR (1,3 & 6) efficiently binds with the viral SPIKE protein, suggesting them as targets for viral infection. Furthermore, docking analysis of the anti-AD and anti-DM drugs against LPARs, SPIKE protein, and the LPARs-SPIKE complex revealed promising candidates, including lupron, neflamapimod, and nilotinib, stating the importance of drug repurposing in the drug discovery process. These drugs exhibited the ability to bind and inhibit the LPAR receptor activity and the SPIKE protein and interfere with LPAR-SPIKE protein interaction. Through a combined network and targeted-based therapeutic intervention approach, this study has identified several drugs that could be repurposed for treating COVID-19 due to their expected interference with LPAR(1, 3, and 6) and spike protein complexes. In addition, it can also be hypothesized that the co-administration of these identified drugs during COVID-19 infection may not only help mitigate the impact of the virus but also potentially contribute to the prevention or management of post-COVID complications related to AD and DM.

Metabolic Bypass Rescues Aberrant S-nitrosylation-Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons.

In Alzheimer's disease (AD), dysfunctional mitochondrial metabolism is associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild-type and AD mutant human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN), evidence is found for compromised mitochondrial energy in AD using the Seahorse platform to analyze glycolysis and oxidative phosphorylation (OXPHOS). Isotope-labeled metabolic flux experiments revealed a major block in activity in the tricarboxylic acid (TCA) cycle at the α-ketoglutarate dehydrogenase (αKGDH)/succinyl coenzyme-A synthetase step, metabolizing α-ketoglutarate to succinate. Associated with this block, aberrant protein S-nitrosylation of αKGDH subunits inhibited their enzyme function. This aberrant S-nitrosylation is documented not only in AD-hiN but also in postmortem human AD brains versus controls, as assessed by two separate unbiased mass spectrometry platforms using both SNOTRAP identification of S-nitrosothiols and chemoselective-enrichment of S-nitrosoproteins. Treatment with dimethyl succinate, a cell-permeable derivative of a TCA substrate downstream to the block, resulted in partial rescue of mitochondrial bioenergetic function as well as reversal of synapse loss in AD-hiN. These findings have therapeutic implications that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC-based models of AD.

Blood-brain barrier transporters: An overview of function, dysfunction in Alzheimer's disease and strategies for treatment.

The blood-brain-barrier (BBB) has a major function in maintaining brain homeostasis by regulating the entry of molecules from the blood to the brain. Key players in BBB function are BBB transporters which are highly expressed in brain endothelial cells (BECs) and critical in mediating the exchange of nutrients and waste products. BBB transporters can also influence drug delivery into the brain by inhibiting or facilitating the entry of brain targeting therapeutics for the treatment of brain disorders, such as Alzheimer's disease (AD). Recent studies have shown that AD is associated with a disrupted BBB and transporter dysfunction, although their roles in the development in AD are not fully understand. Modulation of BBB transporter activity may pose a novel approach to enhance the delivery of drugs to the brain for enhanced treatment of AD. In this review, we will give an overview of key functions of BBB transporters and known changes in AD. In addition, we will discuss current strategies for transporter modulation for enhanced drug delivery into the brain.

Neuronal Stem Cells from Late-Onset Alzheimer Patients Show Altered Regulation of Sirtuin 1 Depending on Apolipoprotein E Indicating Disturbed Stem Cell Plasticity.

Late-onset Alzheimer's disease (AD) is a complex multifactorial disease. The greatest known risk factor for late-onset AD is the E4 allele of the apolipoprotein E (APOE), while increasing age is the greatest known non-genetic risk factor. The cell type-specific functions of neural stem cells (NSCs), in particular their stem cell plasticity, remain poorly explored in the context of AD pathology. Here, we describe a new model that employs late-onset AD patient-derived induced pluripotent stem cells (iPSCs) to generate NSCs and to examine the role played by APOE4 in the expression of aging markers such as sirtuin 1 (SIRT1) in comparison to healthy subjects carrying APOE3. The effect of aging was investigated by using iPSC-derived NSCs from old age subjects as healthy matched controls. Transcript and protein analysis revealed that genes were expressed differently in NSCs from late-onset AD patients, e.g., exhibiting reduced autophagy-related protein 7 (ATG7), phosphatase and tensin homolog (PTEN), and fibroblast growth factor 2 (FGF2). Since SIRT1 expression differed between APOE3 and APOE4 NSCs, the suppression of APOE function in NSCs also repressed the expression of SIRT1. However, the forced expression of APOE3 by plasmids did not recover differently expressed genes. The altered aging markers indicate decreased plasticity of NSCs. Our study provides a suitable in vitro model to investigate changes in human NSCs associated with aging, APOE4, and late-onset AD.

Quercetin-1,2,3-Triazole Hybrids as Multifunctional Anti-Alzheimer's Agents.

The number of patients with Alzheimer's disease (AD) continues to rise and, despite the efforts of researchers, there are still no effective treatments for this multifaceted disease. The main objective of this work was the search for multifunctional and more effective anti-Alzheimer agents. Herein, we report the evaluation of a library of quercetin-1,2,3-triazole hybrids (I-IV) in antioxidant, hydrogen peroxide-induced oxidative stress protection, and cholinesterases (AChE and BuChE) inhibitory activities. Hybrids IIf and IVa-d showed potent in vitro inhibitory activity on eqBuChE (IC50 values between 11.2 and 65.7 µM). Hybrid IIf, the best inhibitor, was stronger than galantamine, displaying an IC50 value of 11.2 µM for eqBuChE, and is also a competitive inhibitor. Moreover, toxicity evaluation for the most promising hybrids was performed using the Artemia salina toxicity assay, showing low toxicity. Hybrids IIf, IVb, and IVd did not affect viability at 12.5 µM and also displayed a protective effect against oxidative stress induced by hydrogen peroxide in cell damage in MCF-7 cells. Hybrids IIf, IVb, and IVd act as multifunctional ligands in AD pathologies.

Potential use of iPSCs for disease modeling, drug screening, and cell-based therapy for Alzheimer's disease.

Alzheimer's disease (AD) is a chronic illness marked by increasing cognitive decline and nervous system deterioration. At this time, there is no known medication that will stop the course of Alzheimer's disease; instead, most symptoms are treated. Clinical trial failure rates for new drugs remain high, highlighting the urgent need for improved AD modeling for improving understanding of the underlying pathophysiology of disease and improving drug development. The development of induced pluripotent stem cells (iPSCs) has made it possible to model neurological diseases like AD, giving access to an infinite number of patient-derived cells capable of differentiating neuronal fates. This advance will accelerate Alzheimer's disease research and provide an opportunity to create more accurate patient-specific models of Alzheimer's disease to support pathophysiological research, drug development, and the potential application of stem cell-based therapeutics. This review article provides a complete summary of research done to date on the potential use of iPSCs from AD patients for disease modeling, drug discovery, and cell-based therapeutics. Current technological developments in AD research including 3D modeling, genome editing, gene therapy for AD, and research on familial (FAD) and sporadic (SAD) forms of the disease are discussed. Finally, we outline the issues that need to be elucidated and future directions for iPSC modeling in AD.

Understanding Alzheimer's Disease and its Metal Chelation Therapeutics: A Narrative Review.

The neurodegenerative disorders are age-related illnesses that cause the morphology or activity of neurons to deteriorate over time. Alzheimer's disease is the most frequent neurodegenerative illness in the long run. The rate of advancement might vary, even though it is a progressive neurological illness. Various explanations have been proposed, however the true etiology of Alzheimer's disease remains unclear. Most pharmacological interventions are based on the cholinergic theory, that is earliest idea. In accordance with the amyloid hypothesis, the buildup of beta-amyloid in brain regions is the primitive cause of illness. There is no proof that any one strategy is useful in avoiding Alzheimer's disease, though some epidemiological studies have suggested links within various modifiable variables, such as cardiovascular risk, diet and so on. Different metals like zinc, iron, and copper are naturally present in our bodies. In metal chelation therapy drugs are used to jam the metal ions from combining with other molecules in the body. Clioquinol is one of the metal chelation drugs used by researchers. Research on metal chelation is still ongoing. In the present review, we go over the latest developments in prevalence, incidence, etiology, or pathophysiology of our understanding of Alzheimer's disease. Additionally, a brief discussion on the development of therapeutic chelating agents and their viability as Alzheimer's disease medication candidates is presented. We also assess the effect of clioquinol as a potential metal chelator.

Neurochemical Research of LOXBlock-1 and ZnSO4 against Neurodegenerative Damage Induced by Amyloid Beta(1-42).

Synaptosomes offer an intriguing ex vivo model system for investigating the molecular mechanisms of neurodegenerative processes. Lipoxygenases significantly affect the course of neurodegenerative diseases. Homeostasis of trace elements such as zinc is necessary for the continuity of brain functions. In this study, we purpose to determine whether LOXBlock-1, a 12/15 lipoxygenase inhibitor, and zinc sulfate (ZnSO4) provide any biochemical protection during neurodegenerative damage in synaptosomes induced by amyloid beta 1-42 (Aß1-42). In this study, animals (30 Wistar Albino male rats 30) were divided into 5 groups (6 animals in each group): Control, 10µM Aß1-42, 10µM Aß1-42+25mM LOXBlock-1, 10µM Aß1-42+10µM ZnSO4, and 10µM Aß1-42+25mM LOXBlock-1+10µM ZnSO4. Synaptosomes were isolated from the rat cerebral cortex. Following, 8-hydroxy-2-deoxyguanosine (8-OHdG) levels, malondialdehyde (MDA) levels, adenosine deaminase (ADA) levels, reduced-glutathione (GSH) levels, neuronal nitric oxide synthase (nNOS) levels, acetylcholinesterase (AChE) activity, catalase (CAT) activity, and 8-OHdG levels in synaptosomes were detected according to the ELISA method. ADA and AChE expression and protein levels were analyzed. MDA, nNOS, AChE, and 8-OHdG levels in synaptosomes treated with Aß1-42 resulted in an increase, while there was a decrease in ADA, GSH, and CAT levels (p<0.001 vs. control). Conversely, LOXBlock-1 and ZnSO4 treatments in synaptosomes treated with Aß1-42 decreased MDA, nNOS, AChE, and 8-OHdG levels, while ADA, GSH, and CAT levels increased. Moreover, the most effective improvement was seen in the co-treatment group of LOXBlock-1 and ZnSO4. Our data showed that LOXBlock-1 and ZnSO4 co-treatment may protect against Aß1-42 exposure in rat brain synaptosomes.

Integrating single-nucleus sequence profiling to reveal the transcriptional dynamics of Alzheimer's disease, Parkinson's disease, and multiple sclerosis.

BACKGROUND: Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) are three nervous system diseases that partially overlap clinically and genetically. However, bulk RNA-sequencing did not accurately detect the core pathogenic molecules in them. The availability of high-quality single cell RNA-sequencing data of post-mortem brain collections permits the generation of a large-scale gene expression in different cells in human brain, focusing on the molecular features and relationships between diseases and genes. We integrated single-nucleus RNA-sequencing (snRNA-seq) datasets of human brains with AD, PD, and MS to identify transcriptomic commonalities and distinctions among them. METHODS: The snRNA-seq datasets were downloaded from Gene Expression Omnibus (GEO) database. The Seurat package was used for snRNA-seq data processing. The uniform manifold approximation and projection (UMAP) were utilized for cluster identification. The FindMarker function in Seurat was used to identify the differently expressed genes. Functional enrichment analysis was carried out using the Gene Set Enrichment Analysis (GSEA) and Gene ontology (GO). The protein-protein interaction (PPI) analysis of differentially expressed genes (DEGs) was analyzed using STRING database ( http://string-db.org ). SCENIC analysis was performed using utilizing pySCENIC (v0.10.0) based on the hg19-tss-centered-10 kb-10species databases. The analysis of potential therapeutic drugs was analyzed on Connectivity Map ( https://clue.io ). RESULTS: The gene regulatory network analysis identified several hub genes regulated in AD, PD, and MS, in which HSPB1 and HSPA1A were key molecules. These upregulated HSP family genes interact with ribosome genes in AD and MS, and with immunomodulatory genes in PD. We further identified several transcriptional regulators (SPI1, CEBPA, TFE3, GRHPR, and TP53) of the hub genes, which has important implications for uncovering the molecular crosstalk among AD, PD, and MS. Arctigenin was identified as a potential therapeutic drug for AD, PD, and MS. CONCLUSIONS: Together, the integrated snRNA-seq data and findings have significant implications for unraveling the shared and unique molecular crosstalk among AD, PD, and MS. HSPB1 and HSPA1A as promising targets involved in the pathological mechanisms of neurodegenerative diseases. Additionally, the identification of arctigenin as a potential therapeutic drug for AD, PD, and MS further highlights its potential in treating these neurological disorders. These discoveries lay the groundwork for future research and interventions to enhance our understanding and treatment of AD, PD, and MS.

Outpatient opioid prescribing by Alzheimer's diagnosis among older adults with pain in United States.

OBJECTIVE: To examine opioid prescribing practices for pain in older adults with and without Alzheimer's Disease and Related Dementias (ADRD). METHODS: This cross-sectional study used National Ambulatory Medical Care Survey data (2014-2016, and 2018). Adults aged ≥ 50 years with pain were analyzed. Prescribing of opioid and concomitant sedative prescriptions (including benzodiazepines, Z-drugs, and barbiturates) were identified by the Multum lexicon code. Multivariable logistic regression evaluated the risk of opioid prescribing or co-prescribing of opioid and sedative associated with ADRD in older adults with pain. RESULTS: There were 13,299 office visits in older adults with pain, representing 451.75 million visits. Opioid prescribing occurred in 27.19%; 30% involved co-prescribing of opioids and sedatives. ADRD was not associated with opioid prescribing or co-prescribing of opioid and sedative therapy. CONCLUSIONS: Opioid and sedatives are commonly prescribed in older adults with pain. Longitudinal studies need to understand the etiology and chronicity of opioid use in older patients, specifically with ADRD.

Early Splicing Complexes and Human Disease.

Over the last decade, our understanding of spliceosome structure and function has significantly improved, refining the study of the impact of dysregulated splicing on human disease. As a result, targeted splicing therapeutics have been developed, treating various diseases including spinal muscular atrophy and Duchenne muscular dystrophy. These advancements are very promising and emphasize the critical role of proper splicing in maintaining human health. Herein, we provide an overview of the current information on the composition and assembly of early splicing complexes-commitment complex and pre-spliceosome-and their association with human disease.

The Synergistic Potential of Combining PD-1/PD-L1 Immune Checkpoint Inhibitors with NOD2 Agonists in Alzheimer's Disease Treatment.

Our research over the past decade has compellingly demonstrated the potential of Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) receptor agonists in Alzheimer's disease (AD) treatment. These agonists facilitate the conversation of pro-inflammatory monocytes into patrolling monocytes, leading to the efficient clearance of amyloid-ß (Aß) in the AD-affected cerebrovascular system. This approach surpasses the efficacy of targeting Aß formation, marking a significant shift in therapeutic strategies. Simultaneously, inhibitors of PD-1/PD-L1 immune check point or glycogen synthase kinase 3 beta (GSK3ß), which modulates PD-1, have emerged as potent AD treatment modalities. PD-1 inhibitor exhibits a profound potential in monocytes' recruitment to the AD-afflicted brain. Recent evidence suggests that an integrated approach, combining the modulation of NOD2 and PD-1, could yield superior outcomes. This innovative combinatorial therapeutic approach leverages the potential of MDP to act as a catalyst for the conversion of inflammatory monocytes into patrolling monocytes, with the subsequent recruitment of these patrolling monocytes into the brain being stimulated by the PD-1 inhibitor. These therapeutic interventions are currently under preclinical investigation by pharmaceutical entities, underscoring the promise they hold. This research advocates for the modulation, rather than suppression, of the innate immune system as a promising pharmacological strategy in AD.

Mitochondrial dysfunction and oxidative stress in Alzheimer's disease, and Parkinson's disease, Huntington's disease and Amyotrophic Lateral Sclerosis -An updated review.

Misfolded proteins in the central nervous system can induce oxidative damage, which can contribute to neurodegenerative diseases in the mitochondria. Neurodegenerative patients face early mitochondrial dysfunction, impacting energy utilization. Amyloid-ß and tau problems both have an effect on mitochondria, which leads to mitochondrial malfunction and, ultimately, the onset of Alzheimer's disease. Cellular oxygen interaction yields reactive oxygen species within mitochondria, initiating oxidative damage to mitochondrial constituents. Parkinson's disease, linked to oxidative stress, α-synuclein aggregation, and inflammation, results from reduced brain mitochondria activity. Mitochondrial dynamics profoundly influence cellular apoptosis via distinct causative mechanisms. The condition known as Huntington's disease is characterized by an expansion of polyglutamine, primarily impactingthe cerebral cortex and striatum. Research has identified mitochondrial failure as an early pathogenic mechanism contributing to HD's selective neurodegeneration. The mitochondria are organelles that exhibit dynamism by undergoing fragmentation and fusion processes to attain optimal bioenergetic efficiency. They can also be transported along microtubules and regulateintracellular calcium homeostasis through their interaction with the endoplasmic reticulum. Additionally, the mitochondria produce free radicals. The functions of eukaryotic cells, particularly in neurons, have significantly deviated from the traditionally assigned role of cellular energy production. Most of them areimpaired in HD, which may lead to neuronal dysfunction before symptoms manifest. This article summarizes the most important changes in mitochondrial dynamics that come from neurodegenerative diseases including Alzheimer's, Parkinson's, Huntington's and Amyotrophic Lateral Sclerosis. Finally, we discussed about novel techniques that can potentially treat mitochondrial malfunction and oxidative stress in four most dominating neuro disorders.

Behavioural, genomics and proteomic approach to examine Alzheimer's disease in zebrafish.

Globally around 24 million elderly population are dealing with dementia, and this pathological characteristic is commonly seen in people suffering from Alzheimer's disease (AD). Despite having multiple treatment options that can mitigate AD symptoms, there is an imperative call to advance our understanding of the disease pathogenesis to unfold disease-modifying treatments/therapies. To explore the driving mechanisms of AD development, we stretch out further to study time-dependant changes after Okadaic acid (OKA)-induced AD-like conditions in zebrafish. We evaluated the pharmacodynamics of OKA at two-time points, i.e., after 4-days and 10-days exposure to zebrafish. T-Maze was utilized to observe the learning and cognitive behaviour, and inflammatory gene expressions such as 5-Lox, Gfap, Actin, APP, and Mapt were performed in zebrafish brains. To scoop everything out from the brain tissue, protein profiling was performed using LCMS/MS. Both time course OKA-induced AD models have shown significant memory impairment, as evident from T-Maze. Gene expression studies of both groups have reported an overexpression of 5-Lox, GFAP, Actin, APP, and OKA 10D group has shown remarkable upregulation of Mapt in zebrafish brains. In the case of protein expression, the heatmap suggested an important role of some common proteins identified in both groups, which can be explored further to investigate their mechanism in OKA-induced AD pathology. Presently, the preclinical models available to understand AD-like conditions are not completely understood. Hence, utilizing OKA in the zebrafish model can be of great importance in understanding the pathology of AD progression and as a screening tool for drug discovery.

Connecting the Gut Microbiota and Neurodegenerative Diseases: the Role of Bile Acids.

With the acceleration of global population aging, neurodegenerative diseases (NDs) will become the second leading cause of death in the world, which seriously threatens human life and health. Alzheimer's disease and Parkinson's disease are the most common and typical NDs. The exact mechanisms of the NDs occurrence and development remain unclear, which may be related to immune, oxidative stress, and abnormal aggregation of pathogenic proteins. Studies have suggested that gut microbiota (GM) influences brain function and plays an important role in regulating emotional and cognitive function. Recently, bile acids (BAs) have become the "star molecule" in the microbiota-gut-brain (MGB) axis research. BAs have been reported to exert anti-inflammatory, antioxidant, and neuroprotective activities in NDs. However, the role of BAs in the connection between GM and the central nervous system (CNS) is still unclear. In this review, we will review the possible mechanisms of BAs between GM and NDs and explore the function of BAs to provide ideas for the prevention and treatment of NDs in the future.