Hyperphosphorylation Of Protein Research Articles

The phospho-tau cascade, basal forebrain neurodegeneration, and dementia in Alzheimer's disease: Anti-neurodegenerative benefits of acetylcholinesterase inhibitors.

A conundrum in Alzheimer's disease (AD) is why the long-term use of acetylcholinesterase (AChE) inhibitors, intended for treatment of dementia, results in slowing neurodegeneration in the cholinergic basal forebrain, hippocampus, and cortex. The phospho-tau cascade hypothesis presented here attempts to answer that question by unifying three hallmark features of AD into a specific sequence of events. It is proposed that the hyperphosphorylation of tau protein leads to the AD-associated deficit of nerve growth factor (NGF), then to atrophy of the cholinergic basal forebrain and dementia. Because the release of pro-nerve growth factor (pro-NGF) is activity-dependent and is controlled by basal forebrain projections to the hippocampus and cortex, our hypothesis is that AChE inhibitors act by increasing acetylcholine-dependent pro-NGF release and, thus, augmenting the availability of mature NGF and improving basal forebrain survival. If correct, improved central nervous system-selective AChE inhibitor therapy started prophylactically, before AD-associated basal forebrain atrophy and cognitive impairment onset, has the potential to delay not only the onset of dementia but also its rate of advancement. The phospho-tau hypothesis thus suggests that preventing hyperphosphorylation of tau protein, early should be a high priority as a strategy to help reduce dementia and its associated widespread social and economic suffering.

A Comprehensive Analysis on Galantamine Based Hybrids for the Management of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive chronic age-related neurodegenerative brain disorder characterized by the loss of memory and other cognitive functions. The exact etiology of AD is still under investigation, however several factors such as low level of neurotransmitter acetylcholine (ACh), aggregation of amyloid beta (Aβ) in the form of Aβ plaques, hyperphosphorylation of tau protein into neurofibrillary tangles (NFTs), oxidative stress, and metal ion imbalance are the major hallmarks of this disease. Of the multiple hypotheses for AD, the amyloid-β (Aβ) and cholinergic hypothesis are the main targeting hypotheses for AD. Some researchers hypothesized that the primary event associated with the cholinergic neurotransmitter (acetylcholine) is memory loss and cognitive impairment. Due to the disease's complicated pathogenesis, long-term therapy with a single target candidate is futile. As a result, multitargeted and multifunctional therapies have emerged. Various research teams are concentrating on addressing multiple disease factors through hybridization techniques. Consequently, this hybridization approach has been applied to all core scaffolds, including galantamine. In this article, we tried to provide a thorough overview of the most recent developments on galantamine, a prospective AChE inhibitor, and its hybrid analogs as possible therapeutic agents for treating AD. Furthermore, we also provided the design, synthesis, and SAR analysis of the galantamine-based compounds used in the last decades for the management of AD.

Lysine Acetyltransferase TIP60 Restricts Nerve Injury by Activating IKKβ/SNAP23 Axis-Mediated Autophagosome-Lysosome Fusion in Alzheimer's Disease.

The hyperphosphorylation of Tau protein is considered an important cause of neuronal degeneration in Alzheimer's disease (AD). The disruption of neuronal histone acetylation homeostasis mediated by Tip60 HAT is a common early event in neurodegenerative diseases, but the deeper regulatory mechanism on β-amyloid peptide (Aβ)-induced neurotoxicity and autophagic function in AD is still unclear. AD models were established both in APP/PS1 mice and Aβ1-42-treated SH-SY5Y cells. The Morris water maze test (MWM) was performed to examine mouse cognitive function. Neurological damage in the hippocampus was observed by hematoxylin-eosin (H&E), Nissl's, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and NeuN staining. Autophagosome-lysosome fusion was detected by immunohistochemistry, immunofluorescence, and Lyso-Tracker Red staining. Cell viability and apoptosis were evaluated by CCK-8 assay and flow cytometry. The molecular interactions were verified by co-immunoprecipitation (Co-IP), dual luciferase assays, and ChIP detections. The RNA and autophagy-lysosome-related proteins were assessed by Western blot and RT-qPCR. TIP60 overexpression improved cognitive deficits and neurological damage and restored the impairment of autophagy-lysosomes fusion invivo. Similarly, the upregulation of TIP60 in Aβ1-42-treated SH-SY5Y cells suppressed neuronal apoptosis and tau phosphorylation through the activating autophagy-lysosome pathway. Mechanistically, TIP60 activated IKKβ transcription by promoting SOX4 acetylation, thus leading to the translocation of SNAP23 to STX17-contained autophagosomes. Moreover, the protective roles of TIP60 in neuron damage were abolished by the inhibition of SOX4/IKKβ signaling. Collectively, our results highlighted the potential of the TIP60 target for AD and provided new insights into the mechanisms underlying neuroprotection in this disorder.

Alzheimer's Disease Protein Targets: Comprehensive Review and Future Directions.

Alzheimer's disease (AD) is a gradual degenerative ailment of the nervous system that is marked by the buildup of amyloid-β plaques and neurofibrillary tangles. This accumulation causes problems with the connections between nerve cells and the loss of these cells. This review paper explores the complex pathophysiology of AD, analyzing the neuronal loss reported in key brain regions like the entorhinal cortex, amygdala, hippocampus, and cortical association areas. The text also examines subcortical nuclei participation, such as the noradrenergic locus coeruleus, serotonergic dorsal raphe, and cholinergic basal nucleus. Also, this review discusses the importance of tau protein hyperphosphorylation, oxidative stress, and metal ion dysregulation in the evolution of AD. Moreover, it explores the cholinergic theory and the influence of the APOE (apolipoprotein E) genotype on the effectiveness of therapy. This article thoroughly summarizes the current knowledge on AD, including its clinical symptoms and possible treatment approaches, by combining several theories and new targets. The study highlights the connection between the degree of tangle development and the severity of dementia, underlining the need for creative methods to tackle the complex difficulties of discovering drugs for AD.

Exploring the Benzazoles Derivatives as Pharmacophores for AChE, BACE1, and as Anti-Aβ Aggregation to Find Multitarget Compounds against Alzheimer’s Disease

Despite the great effort that has gone into developing new molecules as multitarget compounds to treat Alzheimer’s disease (AD), none of these have been approved to treat this disease. Therefore, it will be interesting to determine whether benzazoles such as benzimidazole, benzoxazole, and benzothiazole, employed as pharmacophores, could act as multitarget drugs. AD is a multifactorial disease in which several pharmacological targets have been identified—some are involved with amyloid beta (Aβ) production, such as beta secretase (BACE1) and beta amyloid aggregation, while others are involved with the cholinergic system as acetylcholinesterase (AChE) and butirylcholinesterase (BChE) and nicotinic and muscarinic receptors, as well as the hyperphosphorylation of microtubule-associated protein (tau). In this review, we describe the in silico and in vitro evaluation of benzazoles on three important targets in AD: AChE, BACE1, and Aβ. Benzothiazoles and benzimidazoles could be the best benzazoles to act as multitarget drugs for AD because they have been widely evaluated as AChE inhibitors, forming π–π interactions with W286, W86, Y72, and F338, as well as in the AChE gorge and catalytic site. In addition, the sulfur atom from benzothiazol interacts with S286 and the aromatic ring from W84, with these compounds having an IC50 value in the μM range. Also, benzimidazoles and benzothiazoles can inhibit Aβ aggregation. However, even though benzazoles have not been widely evaluated on BACE1, benzimidazoles evaluated in vitro showed an IC50 value in the nM range. Therefore, important chemical modifications could be considered to improve multitarget benzazoles’ activity, such as substitutions in the aromatic ring with electron withdrawal at position five, or a linker 3 or 4 carbons in length, which would allow for better interaction with targets.

Dihydroquercetin nanoparticles nasal gel is a promising formulation for amelioration of Alzheimer’s disease

Dihydroquercetin is a natural flavonoid with anti-inflammatory, antioxidant, and neuroprotective activities. Dihydroquercetin exhibits a great neuroprotector promise in Alzheimer’s disorder via preventing the aggregation of amyloid-beta-peptide-Aβ(1–42). The goal of the study was to create dihydroquercetin-loaded-chitosan nanoparticles (DHQ-CS NPs) loaded to a mucoadhesive, thermosensitive in-situ gel for direct nasal administration to cure Alzheimer’s disorder. Loading drug in chitosan nanoparticles and incorporation into thermosensitive gel enhanced residence time and reduced mucociliary-clearance. Different in-vitro-physicochemical-characteristics of gels and nanoparticles-characterization were used to evaluate the formulations. The therapeutic effectiveness of DHQ-CS NPs gel was evaluated behaviorally, biochemically and histopathologically in Alzheimer’s-rat-model compared to intranasal DHQ gel. The small particles-size was obtained = 235.3 nm of DHQ-CS NPs. The DHQ-CS NPs gel demonstrated a greater release rate compared to the raw DHQ gel. Additionally, the nasal-administration of the DHQ-CS NPs gel showed better In-vivo results compared to DHQ gel, through improvement of memory and learning deficits and also the exploratory behavior and new object memory in streptozotocin induced-Alzheimer rats. Biochemically, the intranasal DHQ-CS NPs gel, showed reduced both Aβ-protein formation and tau protein hyperphosphorylation, inhibition of acetylcholine esterase activity and oxidative stress in the brain with increase of total antioxidants in the brain and serum, compared to DHQ gel. Histopathologically, the DHQ-CS NPs nasal gel produced improvement in the hippocampal and cerebral cortex structures, being comparable to the normal group. Consequently, the intranasal DHQ-CS NPs loaded in-situ gel seems to be a promising therapeutic formulation for Alzheimer’s disease medication.

The role of PI3K signaling pathway in Alzheimer's disease.

Alzheimer's disease (AD) is a debilitating progressively neurodegenerative disease. The best-characterized hallmark of AD, which is marked by behavioral alterations and cognitive deficits, is the aggregation of deposition of amyloid-beta (Aβ) and hyper-phosphorylated microtubule-associated protein Tau. Despite decades of experimental progress, the control rate of AD remains poor, and more precise deciphering is needed for potential therapeutic targets and signaling pathways involved. In recent years, phosphoinositide 3-kinase (PI3K) and Akt have been recognized for their role in the neuroprotective effect of various agents, and glycogen synthase kinase 3 (GSK3), a downstream enzyme, is also crucial in the tau phosphorylation and Aβ deposition. An overview of the function of PI3K/Akt pathway in the pathophysiology of AD is provided in this review, along with a discussion of recent developments in the pharmaceuticals and herbal remedies that target the PI3K/Akt signaling pathway. In conclusion, despite the challenges and hurdles, cumulative findings of novel targets and agents in the PI3K/Akt signaling axis are expected to hold promise for advancing AD prevention and treatment.

Synergistic Effect between the APOE ε4 Allele with Genetic Variants of GSK3B and MAPT: Differential Profile between Refractory Epilepsy and Alzheimer Disease.

Temporal Lobe Epilepsy (TLE) is a chronic neurological disorder characterized by recurrent focal seizures originating in the temporal lobe. Despite the variety of antiseizure drugs currently available to treat TLE, about 30% of cases continue to have seizures. The etiology of TLE is complex and multifactorial. Increasing evidence indicates that Alzheimer's disease (AD) and drug-resistant TLE present common pathological features that may induce hyperexcitability, especially aberrant hyperphosphorylation of tau protein. Genetic polymorphic variants located in genes of the microtubule-associated protein tau (MAPT) and glycogen synthase kinase-3β (GSK3B) have been associated with the risk of developing AD. The APOE ε4 allele is a major genetic risk factor for AD. Likewise, a gene-dose-dependent effect of ε4 seems to influence TLE. The present study aimed to investigate whether the APOE ɛ4 allele and genetic variants located in the MAPT and GSK3B genes are associated with the risk of developing AD and drug-resistant TLE in a cohort of the Mexican population. A significant association with the APOE ε4 allele was observed in patients with AD and TLE. Additional genetic interactions were identified between this allele and variants of the MAPT and GSK3B genes.

Unlocking Hope: Therapeutic Advances and Approaches in Modulating the Wnt Pathway for Neurodegenerative Diseases.

Neurodegenerative diseases (NDs) are conditions characterized by sensory, motor, and cognitive impairments due to alterations in the structure and function of neurons in the central nervous system (CNS). Despite their widespread occurrence, the exact causes of NDs remain largely elusive, and existing treatments fall short in efficacy. The Wnt signaling pathway is an emerging molecular pathway that has been linked to the development and progression of various NDs. Wnt signaling governs numerous cellular processes, such as survival, polarity, proliferation, differentiation, migration, and fate specification, via a complex network of proteins. In the adult CNS, Wnt signaling regulates synaptic transmission, plasticity, memory formation, neurogenesis, neuroprotection, and neuroinflammation, all essential for maintaining neuronal function and integrity. Dysregulation of both canonical and non-canonical Wnt signaling pathways contributes to neurodegeneration through various mechanisms, such as amyloid-β accumulation, tau protein hyperphosphorylation, dopaminergic neuron degeneration, and synaptic dysfunction, prompting investigations into Wnt modulation as a therapeutic target to restore neuronal function and prevent or delay neurodegenerative processes. Modulating Wnt signaling has the potential to restore neuronal function and impede or postpone neurodegenerative processes, offering a therapeutic approach for targeting NDs. In this article, the current knowledge about how Wnt signaling works in Alzheimer's disease and Parkinson's disease is discussed. Our study aims to explore the molecular mechanisms, recent discoveries, and challenges involved in developing Wnt-based therapies.

In silico identification of novel CDK4 inhibitors for retinoblastoma

Retinoblastoma is a kind of cancer that mostly affects children's eyes, and this study intends to find drugs that can suppress the protein kinase cyclin-dependent kinase 4 (CDK4). CDK4 overexpression leads to the hyper-phosphorylation of RB tumor suppressor protein, which ultimately results in uncontrolled cell division. Aberration of cell cycle regulation, specifically the excessive expression of transcription factors responsible for uncontrolled cell division causes retinoblastoma progression. Hence, we screened 25,000 kinase-targeted small molecules against CDK-4 by Glide in Maestro, the top 11 were chosen based on docking scores, binding modes, chemical variety, and other parameters. We ran molecular dynamics (MD) simulations of top hits found in the docking studies and determined their free binding energy. This helped us to understand their thermodynamic and dynamic properties, as well as confirm the docking results, finally the two most promising ligands (3396 and 960) were obtained. As a result of our research, we have identified promising new compounds for treating retinoblastoma. To validate the possible therapeutic and preventative effects of this ligand, rigorous experimental validation, animal studies as well as clinical trials would be required.

Alzheimer's Disease as a Membrane Dysfunction Tauopathy? New Insights into the Amyloid Cascade Hypothesis.

The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer's disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ42 anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ42 complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ42 production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ42.

Hydrophilic interaction liquid chromatography: An efficient tool for assessing thorium interaction with phosphorylated biomimetic peptides

In the field of nuclear toxicology, the knowledge of the interaction of actinides (An) with biomolecules is of prime concern in order to elucidate their toxicity mechanism and to further develop selective decorporating agents. In this work, we demonstrated the great potential of hydrophilic interaction liquid chromatography (HILIC) to separate polar thorium (Th) biomimetic peptide complexes, as a key starting point to tackle these challenges. Th4+ was used as plutonium (Pu4+) analogue and pS16 and pS1368 as synthetic di- and tetra-phosphorylated peptides capable of mimicking the interaction sites of these An in osteopontin (OPN), a hyperphosphorylated protein. The objective was to determine the relative affinity of pS16 and pS1368 towards Th4+, and to evaluate the pS1368 selectivity when Th4+ was in competition complexation reaction with UO22+ at physiological pH. To meet these aims, HILIC was simultaneously coupled to electrospray ionization mass spectrometry (ESI-MS) and inductively coupled plasma mass spectrometry (ICP-MS), which allowed to identify online the molecular structure of the separated complexes and quantify them, in a single step. Dedicated HILIC conditions were firstly set up to separate the new dimeric Th2(peptide)2 complexes with good separation resolution (peptide = pS16 or pS1368). By adding pS16 and pS1368 in different proportions relatively to Th4+, we found that lower or equal proportions of pS16 with respect to pS1368 were not sufficient to displace pS1368 from Th2pS13682 and pS16 proportion higher than pS1368 led to the formation of a predominant ternary complex Th2(pS16)(pS1368), demonstrating preferential Th4+ binding to the tetra-phosphorylated peptide. Finally, online identification and quantification of the formed complexes when Th4+ and UO22+ were mixed in equimolar ratio relatively to pS1368 showed that in spite of pS1368 has been specifically designed to coordinate UO22+, pS1368 is also Th4+-selective and exhibits stronger affinity for this latter than for UO22+. Hence, the results gathered through this approach highlight the impact of Th4+ coordination chemistry on its interaction with pS1368 and more widely to its affinity for biomolecules.

Association Between Type 2 Diabetes Mellitus and Alzheimer's Disease: Common Molecular Mechanism and Therapeutic Targets.

Diabetes mellitus (DM) and Alzheimer's disease (AD) rates are rising, mirroring the global trend of an aging population. Numerous epidemiological studies have shown that those with Type 2 diabetes (T2DM) have an increased risk of developing dementia. These degenerative and progressive diseases share some risk factors. To a large extent, the amyloid cascade is responsible for AD development. Neurofibrillary tangles induce neurodegeneration and brain atrophy; this chain reaction begins with hyperphosphorylation of tau proteins caused by progressive amyloid beta (Aβ) accumulation. In addition to these processes, it seems that alterations in brain glucose metabolism and insulin signalling lead to cell death and reduced synaptic plasticity in AD, before the onset of symptoms, which may be years away. Due to the substantial evidence linking insulin resistance in the brain with AD, researchers have coined the name "Type 3 diabetes" to characterize the condition. We still know little about the processes involved, even though current animal models have helped illuminate the links between T2DM and AD. This brief overview discusses insulin and IGF-1 signalling disorders and the primary molecular pathways that may connect them. The presence of GSK-3β in AD is intriguing. These proteins' association with T2DM and pancreatic β-cell failure suggests they might be therapeutic targets for both disorders.

A biomimetic upconversion nanoreactors for near-infrared driven H2 release to inhibit tauopathy in Alzheimer's disease therapy

Abnormal hyperphosphorylation of tau protein is a principal pathological hallmark in the onset of neurodegenerative disorders, such as Alzheimer's disease (AD), which can be induced by an excess of reactive oxygen species (ROS). As an antioxidant, hydrogen gas (H2) has the potential to mitigate AD by scavenging highly harmful ROS such as •OH. However, conventional administration methods of H2 face significant challenges in controlling H2 release on demand and fail to achieve effective accumulation at lesion sites. Herein, we report artificial nanoreactors that mimic natural photosynthesis to realize near-infrared (NIR) light-driven photocatalytic H2 evolution in situ. The nanoreactors are constructed by biocompatible crosslinked vesicles (CVs) encapsulating ascorbic acid and two photosensitizers, chlorophyll a (Chla) and indoline dye (Ind). In addition, platinum nanoparticles (Pt NPs) serve as photocatalysts and upconversion nanoparticles (UCNP) act as light-harvesting antennas in the nanoreacting system, and both attach to the surface of CVs. Under NIR irradiation, the nanoreactors release H2 in situ to scavenge local excess ROS and attenuate tau hyperphosphorylation in the AD mice model. Such NIR-triggered nanoreactors provide a proof-of-concept design for the great potential of hydrogen therapy against AD.

An in-silico approach - molecular docking analysis of flavonoids against GSK-3β and TNF-α targets in Alzheimer’s disease

Introduction Drug development for Alzheimer’s disease has one of the greatest failure rates of any therapeutic field and AD is still incurable. Glycogen synthase kinase-3β is a critical enzyme implicated in the pathogenesis of AD, particularly in the hyperphosphorylation of tau protein, which leads to the formation of neurofibrillary tangles. TNF-α also plays a significant role in the pathogenesis of Alzheimer’s disease by promoting neuroinflammation, contributing to the formation of amyloid plaques and neurofibrillary tangles, impairing synaptic function, and disrupting the balance of neurotrophic factors. Phytomedicine has numerous advantages over synthetic medications, acting multiple mode of action, including being less toxic and having fewer adverse effects. Flavonoids act as a promising therapeutic target for treating Alzheimer’s disease. The present work investigates the anti-AD potentials of 35 flavonoids for the inhibition of GSK-3β and TNF-α. Methods The physicochemical, pharmacokinetic parameters, toxicity profile and drug-likeliness of the selected 35 flavonoids were predicted using SwissADME & OSIRIS data Warrier property explorer web tool. All flavonoids were selected for docking studies on GSK-3β and TNF-α protein using Autodock 4.2.1. Results The predictions of this study suggested that among the selected 35 flavonoids, Top 3 flavonoids, such as Epicatechin gallate −10.93 kcal/mol, Fisetin −9.44 kcal/mol and Eriodictyol −8.54 kcal/mol for GSK-3β targets. TNF-α Fisetin −11.52 kcal/mol, Sterubin −10.87 kcal/mol, Biochainin A −10.69 kcal/mol were compared with standard drug donepezil. Conclusion Therefore, these flavonoids could be utilized as possible leads for the structure-based design in the advancement of new, strong Anti-Alzheimer’s agents. However, more invitro and invivo analyses are required to finally confirm the outcomes of this research.

Chloride intracellular channel 4 blockade improves cognition in mice with Alzheimer's disease: CLIC4 protein expression and tau protein hyperphosphorylation

Numerous academic literature suggests that amyloid-β (Aβ) deposition, tau protein phosphorylation, and irreversible neuronal death are the three major causes of AD. The chloride intracellular channel (CLIC) protein family not only regulates the polarisation of neurons, but also has important implications for neuronal survival. Chloride intracellular channel 4 (CLIC4) can be pathologically activated by cyclin-dependent kinase 5 (Cdk5), which causes a significant increase in the expression of CLIC4 and mediates neuronal apoptosis. CLIC4 knockdown inhibits H2O2-induced neuronal apoptosis; however, the relationship between CLIC4 and AD remains unknown. In the present study, we showed that CLIC4 expression was elevated in the hippocampus of AD mice; knockdown of hippocampal CLIC4 alleviated Aβ25–35-induced cognitive impairment in mice; overexpression of hippocampal CLIC4 accelerated Aβ deposition and tau protein hyperphosphorylation in young AD mice (APP/PS1 mice at three months of age). CLIC4 overexpressing mice had a longer escape latency compared to controls in behavioural testing (Morris water maze and T-maze tests). By Co-immunoprecipitation/mass spectrometry (Co-IP/MS) of HT22 cells to identify proteins that specifically bind to CLIC4, we found interactions with CCAAT enhancer binding protein (C/EBPβ); a critical pathway involved in the development of various neurodegenerative diseases. In addition, the knockdown of hippocampal CLIC4 alleviated AD-like pathology by inhibiting the C/EBPβ/AEP signaling pathway. These data suggest an essential role for high CLIC4 expression in the pathophysiology of AD and reveal that inhibition of CLIC4 expression may provide an opportunity for treatment.

MiR-137-3p mechanisms of action and blood-brain barrier penetrating and neuron-targeting lipid nanoparticles deliver miR-137-3p for the treatment of Alzheimer's disease

IntroductionThis study aimed to investigate the impact of miR-137-3p on the pathogenesis of Alzheimer's disease (AD) and develop a pioneering in vivo delivery method for its therapeutic potential. MethodsThis study was initiated by quantifying the levels of miR-137-3p in both human neuroblastoma cells and a mouse model of AD. Our focus was on elucidating its effects on microtubule (MT) stability, tau protein hyperphosphorylation, synaptic damage, and other hallmark features of AD. To circumvent the risks associated with direct brain injections, a novel drug delivery system was engineered, employing lipid nanoparticles (LNPs) functionalized with rabies virus glycoprotein to facilitate the transcytosis of miR-137-3p across the blood-brain barrier and target its delivery directly to neurons. ResultsThe results confirmed miR-137-3p deficiency in both AD cells and animal models. A protective effect of miR-137-3p on MT stability in the AD model was first observed in SH-SY5Y. We validated that the delivery system could effectively penetrate the blood-brain barrier and target neurons, resulting in a significant increase in miR-137-3p levels in the hippocampus of APP/PS1 mice. Glycogen synthase kinase-3 beta expression in the hippocampus of AD mice was inhibited, suggesting successful treatment of AD in this animal model. DiscussionThis study verified a new mechanism of action of miR-137-3p in AD pathogenesis in cells. By developing an LNPs-based miR-137-3p delivery system, this study offers a novel avenue for treating AD, highlighting miR-137-3p as a key factor in AD pathogenesis and its therapeutic application.

Exploring the Frontier: Antisense Long Non-Coding RNAs as Key Regulators in Alzheimer's Disease.

Alzheimer's Disease (AD) is the most prevalent, costly, and fatal neurodegenerative disorder of this century. Two hallmark features of AD are the anomalous cleavage of amyloid precursor protein (APP), which leads to the accumulation of amyloid-beta (Aβ), and the hyperphosphorylation of tau protein. Despite extensive research efforts, the pathology and pathogenesis of AD remain elusive. Recent investigations have highlighted the close association between antisense long non-coding RNAs (AS-lncRNAs) and various biological and functional aspects of AD. However, many AS-lncRNAs implicated in AD have not yet been comprehensively compiled and discussed. This paper reviews the role of AS-lncRNAs in neurodegenerative diseases, outlines their association with AD, and offers novel insights into the potential applications of antisense RNAs in the diagnosis and treatment of AD.

Self-assembled low molecular weight chitosan-bilobalide microsuspension protects hippocampal toxicity in amyloid beta(25–35) induced mice

Alzheimer's disease (AD) is a progressive neurological disorder and is characterized by the accumulation of amyloid beta (Aβ) peptide and hyperphosphorylated tau as a pathological hallmark. Bilobalide (BB) being a highly hydrophobic compound, has poor aqueous solubility, stability, and brain bioavailability. In the present study, we prepared self-assembled low molecular weight chitosan-bilobalide microsuspension (BBC) and examined its neuroprotective effect against intracerebroventricular induction of Aβ(25–35) toxicity in mice. Results showed that BBC has a particle size of 5.77 µm with a desired zeta potential of +42.2 ± 2 mV. BBC displayed aqueous solubility with sustained release kinetics in vitro and had better intracellular transport (70 %) of BB from BBC in Caco-2 cells. Further, treatment with BBC showed increased content [BBC (10 mg), 83.4 ng; BB (10 mg), 15.8 ng] of BB in brain and alleviated Aβ(25–35) induced memory impairment in mice. Moreover, BBC diminished oxidative stress, neuroinflammation, and synaptic dysfunction in Aβ(25–35) induced AD model. In addition, our western blot data suggested that treatment with BBC ameliorated Aβ(25–35) induced hyperphosphorylation of tau protein through regulation of aberrant phosphorylation of Akt/GSK3β/MAPK pathway. The current study may confirm the application of BBC as an oral supplement in the food and pharmaceutical industries for AD conditions.

Characteristics of streptozotocin-induced and okadaic acid-induced models of Alzheimer's disease

alzheimer's disease is the main cause of dementia in people over the age of 65, which affects millions of patients worldwide. Since the prevalence of this pathology increases significantly with the increase in life expectancy, the societal consequences of Alzheimer's disease will be dire if no effective therapy is developed in the near future. Fundamental experimental work is a mandatory and necessary stage of preclinical research for the safe and effective development of new approaches to the treatment of dementia as part of clinical trials in the future. Streptozotocin is a natural chemical obtained from Streptomyces achromogenes, primarily classified as an antibiotic, the introduction of which leads to the activation of oxidative stress and damage to the myelin sheath. This chemical compound promotes the accumulation of characteristic abnormal proteins, called β-amyloid and tau protein, which leads to imitation of neuropathological, behavioral, metabolic and molecular symptoms that resemble human Alzheimer's disease. Okadaic acid is a C38 fatty acid polyester phycotoxin, which is a powerful and selective inhibitor of serine/threonine phosphatases: PP-1c, PP1, PP2A and PP2B, which leads to a decrease in dephosphorylation of phosphorylated tau protein and, accordingly, to hyperphosphorylation of tau protein. Hyperphosphorylation of tau protein is responsible for the deposition of neurofibrillary tangles in vivo and in vitro, which ultimately causes synaptic dysfunction and neuronal death. In addition, okadaic acid activates kinases that regulate tau protein phosphorylation: GSK3β, CDK5, MAPK, ERK1/2, AMPK. The activation of kinases significantly contributes to the phosphorylation of tau protein. Okadain administration is also reported to significantly activate the expression of BACE1, one of the key enzymes in the amyloidogenic cascade. The mechanisms of molecular and morphological changes of the Alzheimer's type in the brain of experimental animals when streptozotocin and okadaic acid are administered are similar in many respects. These include induction and activation of neurodegeneration, apoptosis and necrosis of neurons, development of oxidative stress and inhibition of antioxidant systems, deficiency of neurotransmitters and mitochondrial dysfunction, etc. Both proposed toxins effectively contribute to the simulation of dementia of the Alzheimer's type in the experiment.