Hyperphosphorylation Of Protein Research Articles

First in Class Dual Non-ATP-Competitive Glycogen Synthase Kinase 3β/Histone Deacetylase Inhibitors as a Potential Therapeutic to Treat Alzheimer's Disease.

Despite recent FDA approvals, Alzheimer's disease (AD) still represents an unmet medical need. Among the different available therapeutic approaches, the development of multitarget molecules represents one of the most widely pursued. In this work, we present a second generation of dual ligands directed toward highly networked targets that are deeply involved in the development of the disease, namely, Histone Deacetylases (HDACs) and Glycogen Synthase Kinase 3β (GSK-3β). The synthesized compounds are highly potent GSK-3β, HDAC2, and HDAC6 inhibitors with IC50 values in the nanomolar range of concentrations. Among them, compound 4 inhibits histone H3 and tubulin acetylation at 0.1 μM concentration, blocks hyperphosphorylation of tau protein, and shows interesting immunomodulatory and neuroprotective properties. These features, together with its ability to cross the blood-brain barrier and its favorable physical-chemical properties, make compound 4 a promising hit for the development of innovative disease-modifying agents.

Stem Cell Interventions in the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD), an inexorable neurodegenerative ailment marked by cognitive impairment and neuropsychiatric manifestations, stands as the foremost prevailing form of dementia in the geriatric population. Its pathological signs include the aggregation of amyloid proteins, hyperphosphorylation of tau proteins, and the consequential loss of neural cells. The etiology of AD has prompted the formulation of numerous conjectures, each endeavoring to elucidate its pathogenesis. While a subset of therapeutic agents has displayed clinical efficacy in AD patients, a significant proportion has encountered disappointment. Notably, the extent of neural cell depletion bears a direct correlation with the disease's progressive severity. However, the absence of efficacious therapeutic remedies for neurodegenerative afflictions engenders a substantial societal burden and exerts a notable economic toll. In the past two decades, the realm of regenerative cell therapy, referred to as stem cell therapy, has unfolded as an avenue for the exploration of profoundly innovative approaches to treat neurodegenerative conditions. This promise is underpinned by the remarkable capacity of stem cells to remediate compromised neural tissue by means of cell replacement, to cultivate an environment conducive to regeneration, and to shield extant healthy neuronal and glial components from further degradation. Thus, this review aims to delve into the current knowledge of stem cell-based therapies and future possibilities in this domain.

Pharmacotherapeutic Potential of Bitter Gourd (Momordica charantia) in Age-related Neurological Diseases.

Due to the growth of the elderly population, age-related neurological disorders are an increasing problem. Aging begins very gradually and later leads to several neurological issues such as lower neurotransmitter levels, oxidative stress, neuronal inflammation, and continual neuronal loss. These changes might contribute to brain disorders such as Alzheimer's disease (AD), dementia or mild cognitive impairment, and epilepsy and glioma, and can also aggravate these disorders if they were previously present. Momordica charantia (bitter gourd), a member of the Cucurbitaceae family, is a good source of carbohydrates, proteins, vitamins, and minerals. It is used for diabetes and known for its hypoglycemic and antioxidant effects. In this review, we discuss the pharmaceutical effects of M. charantia on age-related neurological disorders. We searched several databases, including PubMed and Google Scholar, using MeSH terms. We searched articles published up until 2022 regardless of publication language. M. charantia is rich in luteolin, which increases acetylcholine in neurons by binding to enzymes in acetylcholine metabolism pathways, including butyrylcholinesterase and acetylcholinesterase. This binding inhibits the hyperphosphorylation of tau protein by restraining its kinase enzyme. Furthermore, this substance can lower serum cholesterol and has multi-target activity in AD and memory loss. M. charantia can also improve memory by decreasing tau protein and it also has potent antioxidant activity and anti-inflammatory effects. This review highlights that M. charantia has effects on many age-related neurological disorders, and can be a cost-effective supplement with minimal side effects.

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 (3mg/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 Aβ 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.

Beta-amyloid plaque deposits and increased tau protein in the early diagnosis of alzheimer’s disease: the importance of physical activity in the prevention and evolution of the patient

In recent years, it has become clear that the β-amyloid (Aβ) component of senile plaques may be the key molecule in the pathology of Alzheimer's disease (AD). However, the origin and site of Aβ's neurotoxic action are still the subject of controversy. The precursor of the β-amyloid peptide is the β-amyloid precursor protein, which is predominantly neuronal. The hypothesis is that intraneuronal dysregulation of Amyloid Precursor Protein (APP) leads to the accumulation of Aβ peptides in intracellular compartments. This accumulation impairs the trafficking of APP, which initiates a cascade of pathological changes and causes the degeneration of pyramidal neurons. The increased secretion of Aβ as a function of stressed neurons and degenerated neuron remnants provides seeds for extracellular Aβ aggregates, which induce secondary degenerative events involving neighboring cells such as neurons, astroglia and macrophages/microglia. The benefits of physical exercise to reduce low-grade inflammation and improve cognitive function have become a growing field of interest. Epidemiological research has shown that a sedentary lifestyle intensifies the processes of disability and dependence, and also increases the incidence of chronic diseases. Physical exercise has been inversely associated with high levels of different inflammatory markers. It plays a neurotrophic role, capable of promoting a reduction in the accumulation of β-amyloid peptide and the hyperphosphorylation of tau protein, being an important alternative pathway for reducing the degenerative process, which does not result in the release of pro-inflammatory factors, as well as helping to reduce the levels of pro-inflammatory cytokines and improve peripheral concentrations.

Study on the role and mechanism of Tan IIA in Alzheimer’s disease based on CREB-BDNF-TrkB pathway

The occurrence and development of Alzheimer’s disease (AD) is closely related to neuronal loss, inflammatory response, cholinergic imbalance, and Tau protein hyperphosphorylation. Previous studies have confirmed that Streptozotocin (STZ) can be used to establish a rat model of AD by injecting it into the rat brain via the lateral ventricle. Our previous research showed that Danshentone IIA (Tan IIA) can improve cognitive dysfunction in rats caused by CC chemokine ligand 2, and network pharmacology results show that Tan IIA is very likely to improve AD symptoms through the cyclic adenosine monophosphate response element binding protein (CREB), brain-derived neurotrophic factor (BDNF), and tyrosine kinase receptor protein (TrkB) pathway. The results of the water maze experiment showed that after Tan IIA treatment, the escape latency of AD rats was shortened and the number of platform crossings increased; in the new object recognition experiment, the discrimination index of AD rats significantly increased after treatment; Nissl staining and Tunel staining results showed that Tan IIA increased the number of surviving neurons in the hippocampus of cognitively impaired rats and reduced neuronal apoptosis; Bielschowsky silver staining results showed that Tan IIA reduced neurofibrillary tangles (NFTs) in the AD rats; Tan IIA can reduce the inflammatory response and oxidative stress reaction in the hippocampus of AD rats, and at the same time reduce the activity of acetylcholinesterase. Tan IIA can significantly increase the expression of CREB, BDNF, TrkB in the hippocampal tissue of STZ-injured rats (P < 0.05). These data suggest that Tan IIA may upregulate the expression of the CREB-BDNF-TrkB signaling pathway in the hippocampus of brain tissue, produce anti-neuroinflammatory, antioxidant stress, inhibit neuronal apoptosis effects, and improve cholinergic neurotransmitter disorder induced by STZ, reduce the neuronal damage and learning and memory impairment caused by STZ in rats, and improve the cognitive function of rats.

Diabetic Ketoacidosis Induces Tau Hyperphosphorylation in Rat Brain.

Diabetes mellitus (DM) increases the risk for cognitive impairment and Alzheimer's disease (AD). Diabetic ketoacidosis (DKA), a serious complication of DM, may also cause brain damage and further AD, but the underlying molecular mechanisms remain unclear. Our objective was to understand how DKA can promote neurodegeneration in AD. We induced DKA in rats through intraperitoneal injection of streptozotocin, followed by starvation for 48 hours and investigated AD-related brain alterations focusing on tau phosphorylation. We found that DKA induced hyperphosphorylation of tau protein at multiple sites associated with AD. Studies of tau kinases and phosphatases suggest that the DKA-induced hyperphosphorylation of tau was mainly mediated through activation of c-Jun N-terminal kinase and downregulation of protein phosphatase 2A. Disruption of the mTOR-AKT (the mechanistic target of rapamycin-protein kinase B) signaling pathway and increased levels of synaptic proteins were also observed in the brains of rats with DKA. These results shed some light on the mechanisms by which DKA may increase the risk for AD.

Structural Investigations on 2-Amidobenzimidazole Derivatives as New Inhibitors of Protein Kinase CK1 Delta.

Protein kinase CK1δ (CK1δ) is a serine-threonine/kinase that modulates different physiological processes, including the cell cycle, DNA repair, and apoptosis. CK1δ overexpression, and the consequent hyperphosphorylation of specific proteins, can lead to sleep disorders, cancer, and neurodegenerative diseases. CK1δ inhibitors showed anticancer properties as well as neuroprotective effects in cellular and animal models of Parkinson's and Alzheimer's diseases and amyotrophic lateral sclerosis. To obtain new ATP-competitive CK1δ inhibitors, three sets of benzimidazole-2-amino derivatives were synthesized (1-32), bearing different substituents on the fused benzo ring (R) and diverse pyrazole-containing acyl moieties on the 2-amino group. The best-performing derivatives were those featuring the (1H-pyrazol-3-yl)-acetyl moiety on the benzimidazol-2-amino scaffold (13-32), which showed CK1δ inhibitor activity in the low micromolar range. Among the R substituents, 5-cyano was the most advantageous, leading to a compound endowed with nanomolar potency (23, IC50 = 98.6 nM). Molecular docking and dynamics studies were performed to point out the inhibitor-kinase interactions.

LINC00472 regulates ferroptosis of neurons in Alzheimer's disease via FOXO 1.

To explore the molecular mechanism of long non-coding RNA (lncRNA) LINC00472 in Alzheimer's Disease (AD). Ferroptosis-related lncRNAs were screened by GEO database. AD mouse model was constructed for in vivo experimental. The content of Aβ protein and Tau protein hyperphosphorylation were examined in Hippocampal tissue samples of mice. Subsequently, HT22 cells were induced with Aβ25-35 to establish a neuronal injury model of AD in vitro. The expression of FOXO1, a key gene for ferroptosis, was verified by overexpressing/knocking down the LINC00472. The effects of LINC00472 on ROS and lipid peroxidation content, GPX4, and Tau protein in AD model cells were examined by ROS assay, MDA assay, Western Blot and qRT-PCR. Subsequently, the expression of iron ion, FTH, TfRC, and Fpn protein were detected in AD cells. The level of FOXO1 was positively correlated with the degree of AD. In vivo experiments showed that the expression of Aβ and Tau hyperphosphorylated were significantly reduced in the inhibitor group and iron was significantly reduced relative to the AD group. In the AD cell model, the content of lipid peroxide was up-regulated, GPX4 protein and mRNA were decreased, and phosphorylation of Tau protein was enhanced in the AD cell model relative to the control group. Whereas knocking down LINC00472 inhibited the up-regulation of lipid peroxide, decreased the level of GPX4, and enhancement of Tau protein phosphorylation, and it reduced iron accumulation, in AD cells. LINC00472 affects ferroptosis in AD by regulating iron accumulation, in neuronal cells.

Platycodin D Ameliorates Cognitive Impairment in Type 2 Diabetes Mellitus Mice via Regulating PI3K/Akt/GSK3β Signaling Pathway.

Objectives: The aim of this study was to investigate the ameliorative effect of platycodin D (PD) on cognitive dysfunction in type 2 diabetes mellitus (T2DM) and its potential molecular mechanisms of action in vivo and in vitro. Materials and methods: An animal model of cognitive impairment in T2DM was established using a single intraperitoneal injection of streptozotocin (100 mg/kg) after 8 weeks of feeding a high-fat diet to C57BL/6 mice. In vitro, immunofluorescence staining and Western blot were employed to analyze the effects of PD on glucose-induced neurotoxicity in mouse hippocampal neuronal cells (HT22). Results: PD (2.5 mg/kg) treatment for 4 weeks significantly suppressed the rise in fasting blood glucose in T2DM mice, improved insulin secretion deficiency, and reversed abnormalities in serum triglyceride, cholesterol, low-density lipoprotein, and high-density lipoprotein levels. Meanwhile, PD ameliorated choline dysfunction in T2DM mice and inhibited the production of oxidative stress and apoptosis-related proteins of the caspase family. Notably, PD dose-dependently prevents the loss of mitochondrial membrane potential, promotes phosphorylation of phosphatidylinositol 3 kinase and protein kinase B (Akt) in vitro, activates glycogen synthase kinase 3β (GSK3β) expression at the Ser9 site, and inhibits Tau protein hyperphosphorylation. Conclusions: These findings clearly indicated that PD could alleviate the neurological damage caused by T2DM, and the phosphorylation of Akt at Ser473 may be the key to its effect.

Functional Selection of Tau Oligomerization-Inhibiting Aptamers.

Pathological hyperphosphorylation and aggregation of microtubule-associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next-generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (Kd=6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)-induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3β-mediated Tau hyperphosphorylation in cell-free systems and okadaic acid-mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro-orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first-in-class neurotherapeutic to mitigate tauopathy-associated neurodegenerative disorders.

Oxidative Stress, Endoplasmic Reticulum Stress and Apoptosis in the Pathology of Alzheimer's Disease.

Alzheimer's disease (AD) accounts for a major statistic among the class of neurodegenerative diseases. A number of mechanisms have been identified in its pathogenesis and progression which include the amyloid beta (Aβ) aggregation, hyperphosphorylation of tau protein, oxidative stress, endoplasmic reticulum (ER) stress and apoptosis. These processes are interconnected and contribute significantly to the loss of neurons, brain mass and consequential memory loss and other cognitive difficulties. Oxidative stress in AD appears to be caused by excess of oxygen free radicals and extracellular Aβ deposits that cause local inflammatory processes and activate microglia, another possible source of reactive oxygen species (ROS). ER Stress describes the accumulation of misfolded and unfolded proteins as a result of physiological and pathological stimuli including high protein demand, toxins, inflammatory cytokines, and mutant protein expression that disturbs ER homeostasis. When compared to age-matched controls, postmortem brain tissues from AD patients showed elevated levels of ER stress markers, such as PERK, eIF2α, IRE1α, the chaperone Grp78, and the downstream mediator of cell death CHOP. Apoptosis is in charge of eliminating unnecessary and undesired cells to maintain good health. However, it has been demonstrated that a malfunctioning apoptotic pathway is a major factor in the development of certain neurological and immunological problems and diseases in people, including neurodegenerative diseases. This article highlights and discussed some of the experimentally established mechanisms through which these processes lead to the development as well as the exacerbation of AD.

The Different Molecular Targets and Its Significant Role in Alzheimer’s Disease: A Review

Alzheimer's disease is a severe neurodegenerative brain illness that affects the majority of the older population. Alzheimer's disease has become a substantial public health problem due to increased life expectancy in the general population and a better understanding of the disease's socioeconomic effects. This review explores the cholinergic theory, amyloid plaque formation, tau protein hyperphosphorylation, neuroinflammation pathway, oxidative stress, mitochondrial dysfunction, genetic aetiology, infectious pathways, and environmental factors in Alzheimer's disease. Physical and neurological tests, which include intelligence, muscle tone and strength, vision and hearing, and communication, are used to diagnose Alzheimer's disease. In order to make an early diagnosis, brain imaging techniques such as MRI and CT are used. Inflammatory biomarkers like IL-1, IL-6, TNF- α, and TGF- β are all computed in blood testing. The activity of acetylcholinesterase and the concentration of neurotransmitter acetylcholine are measured using a biochemical probe. There is no definite cure, although symptomatic treatment includes cholinesterase inhibitors such as Tacrine, Donepezil, and Rivastigmine, as well as NMDA antagonists such as Memantine are available. For better efficacy, combination therapy such as cholinesterase inhibitors with antioxidants and a combination of hybrid inhibitors has become preferred. Current research focuses on establishing various causes of disease and generating more effective, target-oriented pharmaceutical treatments.

Trans- and Cis-Phosphorylated Tau Protein: New Pieces of the Puzzle in the Development of Neurofibrillary Tangles in Post-Ischemic Brain Neurodegeneration of the Alzheimer's Disease-like Type.

Recent evidence indicates that experimental brain ischemia leads to dementia with an Alzheimer's disease-like type phenotype and genotype. Based on the above evidence, it was hypothesized that brain ischemia may contribute to the development of Alzheimer's disease. Brain ischemia and Alzheimer's disease are two diseases characterized by similar changes in the hippocampus that are closely related to memory impairment. Following brain ischemia in animals and humans, the presence of amyloid plaques in the extracellular space and intracellular neurofibrillary tangles was revealed. The phenomenon of tau protein hyperphosphorylation is a similar pathological feature of both post-ischemic brain injury and Alzheimer's disease. In Alzheimer's disease, the phosphorylated Thr231 motif in tau protein has two distinct trans and cis conformations and is the primary site of tau protein phosphorylation in the pre-entanglement cascade and acts as an early precursor of tau protein neuropathology in the form of neurofibrillary tangles. Based on the latest publication, we present a similar mechanism of the formation of neurofibrillary tangles after brain ischemia as in Alzheimer's disease, established on trans- and cis-phosphorylation of tau protein, which ultimately influences the development of tauopathy.

Firing Alterations of Neurons in Alzheimer's Disease: Are They Merely a Consequence of Pathogenesis or a Pivotal Component of Disease Progression?

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, yet its underlying causes remain elusive. The conventional perspective on disease pathogenesis attributes alterations in neuronal excitability to molecular changes resulting in synaptic dysfunction. Early hyperexcitability is succeeded by a progressive cessation of electrical activity in neurons, with amyloid beta (Aβ) oligomers and tau protein hyperphosphorylation identified as the initial events leading to hyperactivity. In addition to these key proteins, voltage-gated sodium and potassium channels play a decisive role in the altered electrical properties of neurons in AD. Impaired synaptic function and reduced neuronal plasticity contribute to a vicious cycle, resulting in a reduction in the number of synapses and synaptic proteins, impacting their transportation inside the neuron. An understanding of these neurophysiological alterations, combined with abnormalities in the morphology of brain cells, emerges as a crucial avenue for new treatment investigations. This review aims to delve into the detailed exploration of electrical neuronal alterations observed in different AD models affecting single neurons and neuronal networks.

Acromegalic Rat Model Presented Cognitive Impairments and Tau Hyperphosphorylation in Hippocampus.

Acromegaly patients, in addition to the most prominent physical and endocrine changes, also exhibit a higher risk of cognitive dysfunction. However, the reasons and mechanisms underlying cognitive impairments in acromegaly patients remain unknown. Acromegalic rats were induced by subcutaneous injection of tumor cells, with continuous monitoring of body weight and hormonal to confirm the occurrence of acromegaly. Behavioral assessments, including Open Field Test, Novel Object Recognition Test, and Barnes maze Test, were conducted to evaluate the animals' cognitive function. Western blotting, immunohistochemistry, and immunofluorescence techniques were employed to examine changes in hippocampal tau protein, Aβ, and associated signaling pathways. The tumor cells secreting growth hormone increased the secretion of growth hormone, resulting in changes in body size and endocrine functions, thus causing acromegaly. The acromegaly model showed deficiencies in working memory and spatial memory. Hyperphosphorylation of tau protein was observed in the hippocampus of the acromegaly model, but no Aβ deposition was observed. The acromegaly model exhibits hippocampal growth hormone (GH) resistance, decreased expression of GH receptors, and subsequently reduced expression activity of the PI3K-Akt-GSK3β signaling pathway, which is responsible for the hyperphosphorylation of tau protein. The prolonged elevation of GH and insulin-like growth factor 1 (IGF-1) levels caused by acromegaly may lead to abnormalities in the SD rat's PI3K-Akt-GSK3β signaling pathway, subsequently resulting in hyperphosphorylation of hippocampal tau protein and cognitive impairment.

Protective Effect of Ferulic Acid on Acetylcholinesterase and Amyloid Beta Peptide Plaque Formation in Alzheimer's Disease: An In Vitro Study.

Aim This study aims to comprehensively evaluate the effects of ferulic acid (FA) on acetylcholinesterase (AChE) enzyme activity and amyloid beta (Aβ) peptide plaque formation in an in vitro model of Alzheimer's disease (AD). Background ADis a progressive neurological condition marked by disrupted cholinergic signaling, accumulation of Aβ peptide, and tau protein hyperphosphorylation. Currently, no direct anti-Alzheimer drug that effectively prevents the cognitive decline from AD has been reported. To combat this, a multi-target drug addressing several molecular aspects would be ideal for AD. Natural compounds are preferred over synthetic drugs due to their accessibility, cost-efficiency, and lower toxicity The proven association between polyphenolconsumption and the prevention of AD has led to the investigation of the effect of FA, a polyphenolic compound, on acetylcholinesterase enzyme activity and Aβ peptide formation, the key targets of AD. Materials and method The free radical scavenging ability of FA was assessed by xanthine oxidase inhibitory activity. Furthermore, FA was also evaluated for its inhibitory activity against AChE enzyme and amyloid beta peptide formation to evaluate the neuroprotective potential of FA. Results The results showed that FA has the potential to be an AChE inhibitor, thus helping in blocking the activity of AChE and also reducing the incidence of amyloid beta plaque formation. Furthermore, the compound also exhibited a significant antioxidant property which was demonstrated by the xanthine oxidase enzyme inhibitory effect. Conclusion From the observed results, FA has significant antioxidant and neuroprotective effects which are compared with those of their respective standards. More research is required to determine the efficacy and safety of this compound as a treatment for neurodegenerative diseases like AD because the precise mechanism and degree of its AChE inhibitory effects in the brain are still elusive. A potent, selective, and effective drug is desperately needed to treat patients with AD and those at risk of developing the disease.

HIF-1α is a "brake" in JNK-mediated activation of amyloid protein precursor and hyperphosphorylation of tau induced by T-2 toxin in BV2 cells.

Mycotoxins have been shown to activate multiple mechanisms that may potentially lead to the progression of Alzheimer's disease (AD). Overexpression/aberrant cleavage of amyloid precursor protein (APP) and hyperphosphorylation of tau (P-tau) is hallmark pathologies of AD. Recent advances suggest that the neurotoxic effects of mycotoxins involve c-Jun N-terminal kinase (JNK) and hypoxia-inducible factor-1α (HIF-1α) signaling, which are closely linked to the pathogenesis of AD. Due to the high toxicity and broad contamination of T-2 toxin, we assessed how T-2 toxin exposure alters APP and P-tau formation in BV2 cells and determined the underlying roles of HIF-1α and JNK signaling. The findings revealed that T-2 toxin stimulated the expression of HIF-1α and hypoxic stress factors in addition to increasing the expression of APP and P-tau. Additionally, HIF-1α acted as a "brake" on the induction of APP and P-tau expression by negatively regulating these proteins. Notably, T-2 toxin activated JNK signaling, which broke this "brake" to promote the formation of APP and P-tau. Furthermore, the cytoskeleton was an essential target for T-2 toxin to exert cytotoxicity, and JNK/HIF-1α participated in this damage. Collectively, when the T-2 toxin induces the production of APP and P-tau, JNK might interfere with HIF-1α's protective function. This study will provide clues for further research on the neurotoxicity of mycotoxins.

The oral-brain axis: can periodontal pathogens trigger the onset and progression of Alzheimer's disease?

Alzheimer's disease (AD) is the most prevalent form of dementia, characterized by a progressive cognitive decline. Sporadic AD, accounting for more than 95% of cases, may arise due to the influence of environmental factors. It was reported that periodontitis, a common oral ailment, shares several risk factors with AD, including advanced age, smoking, diabetes, and hypertension, among others. Periodontitis is an inflammatory disease triggered by dysbiosis of oral microorganisms, whereas Alzheimer's disease is characterized by neuroinflammation. Many studies have indicated that chronic inflammation can instigate brain AD-related pathologies, including amyloid-β plaques, Tau protein hyperphosphorylation, neuroinflammation, and neurodegeneration. The potential involvement of periodontal pathogens and/or their virulence factors in the onset and progression of AD by the oral-brain axis has garnered significant attention among researchers with ongoing investigations. This review has updated the periodontal pathogens potentially associated with AD, elucidating their impact on the central nervous system, immune response, and related pathological processes in the brain to provide valuable insights for future research on the oral-brain axis.

Generation of tau dephosphorylation-targeting chimeras for the treatment of Alzheimer’s disease and related tauopathies

Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease (AD) and many other tauopathies. Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases. We have conceptualized a strategy, named dephosphorylation-targeting chimeras (DEPTACs), for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation. Here, we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau. Specifically, for one of the selected chimeras, D16, we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro. Moreover, intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice. These results suggested DEPTACs as targeted modulators of tau phosphorylation, which hold therapeutic potential for AD and other tauopathies.