Reduced Tau Hyperphosphorylation Research Articles

Association between Female Reproductive Factors and Risk of Dementia.

Women have an over 50% greater risk of dementia than men, which is a main topic of much research. This review aims to investigate the impact of a woman's reproductive history on dementia risk. The consequences of stillbirth are long-term health and psychosocial problems for women. Because of the awareness of an endangered pregnancy, many parents experience deep anxiety and stress in subsequent pregnancies. There are contradictory conclusions from research about abortion and the risk of dementia correlation. When it comes to the late age of first birth, which is said to be above 35 years old, it was observed that older mothers have a decreased risk of dementia compared to those who gave birth in their 20s; however, being a child of the older mother is connected with a higher risk of developing dementia. Using hormonal contraception can result in decreased risk of dementia as estrogen stimulates microglia-related Aβ removal and reduces tau hyperphosphorylation. The influence of postmenopausal hormonal therapy and the duration of the reproductive period on developing dementia remains unclear. Although female disorders like endometriosis and polycystic ovary syndrome are reported to increase the risk of dementia, the research on this topic is very limited, especially when it comes to endometriosis, and needs further investigation. Interestingly, there is no conclusion on whether hypertensive disorders of pregnancy increase the risk of dementia, but most articles seem to confirm this theory.

Structural determinants for activation of the Tau kinase CDK5 by the serotonin receptor 5-HT7R

BackgroundMultiple neurodegenerative diseases are induced by the formation and deposition of protein aggregates. In particular, the microtubule-associated protein Tau leads to the development of so-called tauopathies characterized by the aggregation of hyperphosphorylated Tau within neurons. We recently showed that the constitutive activity of the serotonin receptor 7 (5-HT7R) is required for Tau hyperphosphorylation and aggregation through activation of the cyclin-dependent kinase 5 (CDK5). We also demonstrated physical interaction between 5-HT7R and CDK5 at the plasma membrane suggesting that the 5-HT7R/CDK5 complex is an integral part of the signaling network involved in Tau-mediated pathology.MethodsUsing biochemical, microscopic, molecular biological, computational and AI-based approaches, we investigated structural requirements for the formation of 5-HT7R/CDK5 complex.ResultsWe demonstrated that 5-HT7R domains responsible for coupling to Gs proteins are not involved in receptor interaction with CDK5. We also created a structural model of the 5-HT7R/CDK5 complex and refined the interaction interface. The model predicted two conserved phenylalanine residues, F278 and F281, within the third intracellular loop of 5-HT7R to be potentially important for complex formation. While site-directed mutagenesis of these residues did not influence Gs protein-mediated receptor signaling, replacement of both phenylalanines by alanine residues significantly reduced 5-HT7R/CDK5 interaction and receptor-mediated CDK5 activation, leading to reduced Tau hyperphosphorylation and aggregation. Molecular dynamics simulations of 5-HT7R/CDK5 complex for wild-type and receptor mutants confirmed binding interface stability of the initial model.ConclusionsOur results provide a structural basis for the development of novel drugs targeting the 5-HT7R/CDK5 interaction interface for the selective treatment of Tau-related disorders, including frontotemporal dementia and Alzheimer’s disease.

Palmatine improves cognitive dysfunction in Alzheimer's disease model rats through autophagy pathway and regulation of gut microbiota

Alzheimer’s disease (AD) is a primary degenerative encephalopathy that first appeared as a decline in memory and learning skills. Over time, the condition's severity grew. Palmatine (Pal) alleviates Alzheimer's disease symptoms, which has neuroprotective benefits. Numerous investigations have demonstrated a close relationship among AD and gut structure changes. The aim of the research was investigating whether the improvement of Pal on AD is linked to regulating gut flora and autophagy. First, we used Aβ1-40 to induce apoptosis in HT22 cells. After Pal treatment, apoptosis can be improved. Then, We used bilateral intracranial hippocampal injection of Aβ1-40 for establishing the AD model, after treatment with Pal, the morris water maze experiment and eight-arm maze test demonstrated that Pal enhanced the AD rats' capacity for learning and memory, HE staining illustrated that Pal improved the morphological abnormalities of brain cells and gut tissue damage. Pal reduced the death of hippocampus neurons, as shown by Nissl staining. Pal substantially reduced Tau hyperphosphorylation and Aβ accumulation in the brain, according to immunohistochemical labelling. Pal improved the expression of LC3, Beclin 1, AMPK, and suppressed the expression of mTOR and P62, as validated by RT-qPCR and immunofluorescence labelling. This suggests that Pal's treatment of AD may be associated with the control of the AMPK/mTOR autophagy signalling system. 16S rRNA sequencing and short-chain fatty acids (SCFAs) content detection analysis illustrated that Pal has the potential to enhance the content of SCFAs, reverse the alterations in gut microorganisms. It has been showed by the study that Pal could improve AD by activating autophagy signaling pathway and improving gut barrier changes.

Fosgonimeton attenuates amyloid-beta toxicity in preclinical models of Alzheimer's disease

Positive modulation of hepatocyte growth factor (HGF) signaling may represent a promising therapeutic strategy for Alzheimer's disease (AD) based on its multimodal neurotrophic, neuroprotective, and anti-inflammatory effects addressing the complex pathophysiology of neurodegeneration. Fosgonimeton is a small-molecule positive modulator of the HGF system that has demonstrated neurotrophic and pro-cognitive effects in preclinical models of dementia. Herein, we evaluate the neuroprotective potential of fosgonimeton, or its active metabolite, fosgo-AM, in amyloid-beta (Aβ)-driven preclinical models of AD, providing mechanistic insight into its mode of action. In primary rat cortical neurons challenged with Aβ (Aβ1-42), fosgo-AM treatment significantly improved neuronal survival, protected neurite networks, and reduced tau hyperphosphorylation. Interrogation of intracellular events indicated that cortical neurons treated with fosgo-AM exhibited a significant decrease in mitochondrial oxidative stress and cytochrome c release. Following Aβ injury, fosgo-AM significantly enhanced activation of pro-survival effectors ERK and AKT, and reduced activity of GSK3β, one of the main kinases involved in tau hyperphosphorylation. Fosgo-AM also mitigated Aβ-induced deficits in Unc-like kinase 1 (ULK1) and Beclin-1, suggesting a potential effect on autophagy. Treatment with fosgo-AM protected cortical neurons from glutamate excitotoxicity, and such effects were abolished in the presence of an AKT or MEK/ERK inhibitor. In vivo, fosgonimeton administration led to functional improvement in an intracerebroventricular Aβ25-35 rat model of AD, as it significantly rescued cognitive function in the passive avoidance test. Together, our data demonstrate the ability of fosgonimeton to counteract mechanisms of Aβ-induced toxicity. Fosgonimeton is currently in clinical trials for mild-to-moderate AD (NCT04488419; NCT04886063).

Sildenafil as a Candidate Drug for Alzheimer's Disease: Real-World Patient Data Observation and Mechanistic Observations from Patient-Induced Pluripotent Stem Cell-Derived Neurons.

Alzheimer's disease (AD) is a chronic neurodegenerative disease needing effective therapeutics urgently. Sildenafil, one of the approved phosphodiesterase-5 inhibitors, has been implicated as having potential effect in AD. To investigate the potential therapeutic benefit of sildenafil on AD. We performed real-world patient data analysis using the MarketScan® Medicare Supplemental and the Clinformatics® databases. We conducted propensity score-stratified analyses after adjusting confounding factors (i.e., sex, age, race, and comorbidities). We used both familial and sporadic AD patient induced pluripotent stem cells (iPSC) derived neurons to evaluate the sildenafil's mechanism-of-action. We showed that sildenafil usage is associated with reduced likelihood of AD across four new drug compactor cohorts, including bumetanide, furosemide, spironolactone, and nifedipine. For instance, sildenafil usage is associated with a 54% reduced incidence of AD in MarketScan® (hazard ratio [HR] = 0.46, 95% CI 0.32- 0.66) and a 30% reduced prevalence of AD in Clinformatics® (HR = 0.70, 95% CI 0.49- 1.00) compared to spironolactone. We found that sildenafil treatment reduced tau hyperphosphorylation (pTau181 and pTau205) in a dose-dependent manner in both familial and sporadic AD patient iPSC-derived neurons. RNA-sequencing data analysis of sildenafil-treated AD patient iPSC-derived neurons reveals that sildenafil specifically target AD related genes and pathobiological pathways, mechanistically supporting the beneficial effect of sildenafil in AD. These real-world patient data validation and mechanistic observations from patient iPSC-derived neurons further suggested that sildenafil is a potential repurposable drug for AD. Yet, randomized clinical trials are warranted to validate the causal treatment effects of sildenafil in AD.

Curcumin-derived carbon quantum dots: Dual actions in mitigating tau hyperphosphorylation and amyloid beta aggregation

The amyloid cascade and tau hypotheses both hold significant implications for the pathogenesis of Alzheimer's disease (AD). Curcumin shows potential by inhibiting the aggregation of amyloid beta (Aβ) and reducing tau hyperphosphorylation, however, its use is limited due to issues with solubility and bioavailability. Carbon dots, recognized for their high biocompatibility and optimal water solubility, have demonstrated the capability to inhibit either Aβ or tau aggregation. Nonetheless, their effects on tau hyperphosphorylation are yet to be extensively explored. This study aims to evaluate the water-soluble curcumin-derived carbon quantum dots (Cur-CQDs) synthesized via an eco-friendly method, designed to preserve the beneficial effects of curcumin while overcoming solubility challenges. The synthesis of Cur-CQDs involves a single-step dry heating process using curcumin, resulting in dots that exhibit negligible cytotoxicity to SH-SY5Y cells at the examined concentrations. Notably, Cur-CQDs have shown the ability to simultaneously mitigate Aβ aggregation and tau hyperphosphorylation. Therefore, it is suggested that Cur-CQDs may hold potential for AD treatment, a hypothesis deserving of further research.

Fosgonimeton, a Small‐Molecule Positive Modulator of the HGF/MET System, Attenuates Amyloid‐β – Mediated Toxicity in Primary Neuron Culture

AbstractBackgroundPositive modulation of the hepatocyte growth factor (HGF)/MET system may represent a promising therapeutic strategy for Alzheimer’s disease (AD). Downstream effectors of HGF/MET, such as AKT or ERK, have been shown to activate pro‐survival signaling cascades that counteract pathological components of AD including excitotoxicity, mitochondrial dysfunction, oxidative stress, and protein aggregation. We have previously that fosgonimeton, a small molecule positive modulator of the HGF/MET system, elicits broad neuroprotective effects (Johnston et. al, 2022). Herein, we investigate the mechanism of action by which fosgonimeton induces neuroprotective effects in beta‐amyloid and glutamate‐challenged primary cortical neurons.MethodPrimary rat cortical neurons were treated with the active metabolite of fosgonimeton (fosgo‐AM), challenged with beta‐amyloid (Aβ1‐42; 15 µM) for 24 hours, and co‐immunostained for microtubule‐associated protein‐2 (MAP‐2) and phospho‐tau (AT100). Immunofluorescence analyses were used to determine neuronal survival, neurite network integrity (total neurite length), and phospho‐tau levels. In a separate model, rat cortical neurons were treated with fosgo‐AM and challenged with glutamate (20 µM) for 24 hours, and immunostained for MAP‐2 to determine neuronal survival and neurite network. To elucidate the mechanism of neuroprotection, protein analyses via western blot and homogenous time‐resolved fluorescence were conducted to assay HGF/MET downstream signaling pathways. In addition, the effect of fosgo‐AM on mitochondrial membrane potential (MMP) was assessed in primary cortical neuron culture via fluorescent MMP dye.ResultFosgo‐AM treatment significantly improved survival of cortical neurons, protected neurite networks, and reduced tau hyperphosphorylation after injury with Aβ1‐42. Additionally, fosgo‐AM reduced glutamate‐mediated cortical neuron death and neurite degeneration. Analyses of downstream signaling effects indicate that the neuroprotective effects of fosgo‐AM treatment may, in part, be the result of activation of AKT signaling and subsequent rescue of mitochondrial membrane potential, thereby reducing protein pathology and oxidative stress.ConclusionOur in vitro data demonstrate the address pathological of AD reduce tau . neuroprotective effects of fosgonimeton, in addition to its neurotrophic and pro‐cognitive effects in preclinical models, highlight its therapeutic potential to interrupt disease progression and restore neuronal health. Fosgonimeton is currently in clinical for mild‐to‐moderate AD (NCT04488419; NCT04886063).

Chronic GCPII (glutamate-carboxypeptidase-II) inhibition reduces pT217Tau levels in the entorhinal and dorsolateral prefrontal cortices of aged macaques.

Current approaches for treating sporadic Alzheimer's disease (sAD) focus on removal of amyloid beta 1-42 (Aβ1-42) or phosphorylated tau, but additional strategies are needed to reduce neuropathology at earlier stages prior to neuronal damage. Longstanding data show that calcium dysregulation is a key etiological factor in sAD, and the cortical neurons most vulnerable to tau pathology show magnified calcium signaling, for example in dorsolateral prefrontal cortex (dlPFC) and entorhinal cortex (ERC). In primate dlPFC and ERC, type 3 metabotropic glutamate receptors (mGluR3s) are predominately post-synaptic, on spines, where they regulate cAMP-calcium signaling, a process eroded by inflammatory glutamate carboxypeptidase II (GCPII) actions. The current study tested whether enhancing mGluR3 regulation of calcium via chronic inhibition of GCPII would reduce tau hyperphosphorylation in aged macaques with naturally-occurring tau pathology. Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)),Aged rhesus macaques were treated daily with the GCPII inhibitor, 2-MPPA (2-3-mercaptopropyl-penanedioic acid (2-MPPA)). Aged macaques that received 2-MPPA had significantly lower pT217Tau levels in dlPFC and ERC, and had lowered plasma pT217Tau levels from baseline. pT217Tau levels correlated significantly with GCPII activity in dlPFC. Both 2-MPPA- and vehicle-treated monkeys showed cognitive improvement; 2-MPPA had no apparent side effects. Exploratory CSF analyses indicated reduced pS202Tau with 2-MPPA administration, confirmed in dlPFC samples. These data provide proof-of-concept support that GCPII inhibition can reduce tau hyperphosphorylation in the primate cortices most vulnerable in sAD. GCPII inhibition may be particularly helpful in reducing the risk of sAD caused by inflammation. These data in nonhuman primates should encourage future research on this promising mechanism. Inflammation is a key driver of sporadic Alzheimer's disease.GCPII inflammatory signaling in brain decreases mGluR3 regulation of calcium.Chronic inhibition of GCPII inflammatory signaling reduced pT217Tau in aged monkeys.GCPII inhibition is a novel strategy to help prevent tau pathology at early stages.

Fibroblast growth factor 10 ameliorates neurodegeneration in mouse and cellular models of Alzheimer's disease via reducing tau hyperphosphorylation and neuronal apoptosis.

Alzheimer's disease (AD) is characterized with senile plaques formed by Aβ deposition, and neurofibrillary tangles composed of hyperphosphorylated tau protein, which ultimately lead to cognitive impairment. Despite the heavy economic and life burdens faced by the patients with AD, effective treatments are still lacking. Previous studies have reported the neuroprotective effects of FGF10 in CNS diseases, but its role in AD remains unclear. In this study, we demonstrated that FGF10 levels were reduced in the serum of AD patients, as well as in the brains of 3xTg-AD mice and APPswe-transfected HT22 cells, suggesting a close relationship between FGF10 and AD. Further investigations revealed that intranasal delivery of FGF10 improved cognitive functions in 3xTg-AD mice. Additionally, FGF10 treatment reduced tau hyperphosphorylation and neuronal apoptosis, thereby mitigating neuronal cell damage and synaptic deficits in the cortex and hippocampus of 3xTg-AD mice, as well as APPswe-transfected HT22 cells. Furthermore, we evaluated the therapeutic potential of FGF10 gene delivery for treating AD symptoms and pathologies. Tail vein delivery of the FGF10 gene using AAV9 improved cognitive and neuronal functions in 3xTg-AD mice. Similarly, endogenous FGF10 overexpression ameliorated tau hyperphosphorylation and neuronal apoptosis in the cortex and hippocampus of 3xTg-AD mice. Importantly, we confirmed that the FGFR2/PI3K/AKT signaling pathway was activated following intranasal FGF10 delivery and AAV9-mediated FGF10 gene delivery in 3xTg-AD mice and APPswe-transfected HT22 cells. Knockdown of FGFR2 attenuated the protective effect of FGF10. Collectively, these findings suggest that intranasal delivery of FGF10 and AAV9-mediated FGF10 gene delivery could be a promising disease-modifying therapy for AD.

Alzheimer's Disease and Green Tea: Epigallocatechin-3-Gallate as a Modulator of Inflammation and Oxidative Stress.

Alzheimer's disease (AD) is the most common cause of dementia, characterised by a marked decline of both memory and cognition, along with pathophysiological hallmarks including amyloid beta peptide (Aβ) accumulation, tau protein hyperphosphorylation, neuronal loss and inflammation in the brain. Additionally, oxidative stress caused by an imbalance between free radicals and antioxidants is considered one of the main risk factors for AD, since it can result in protein, lipid and nucleic acid damage and exacerbate Aβ and tau pathology. To date, there is a lack of successful pharmacological approaches to cure or even ameliorate the terrible impact of this disease. Due to this, dietary compounds with antioxidative and anti-inflammatory properties acquire special relevance as potential therapeutic agents. In this context, green tea, and its main bioactive compound, epigallocatechin-3-gallate (EGCG), have been targeted as a plausible option for the modulation of AD. Specifically, EGCG acts as an antioxidant by regulating inflammatory processes involved in neurodegeneration such as ferroptosis and microglia-induced cytotoxicity and by inducing signalling pathways related to neuronal survival. Furthermore, it reduces tau hyperphosphorylation and aggregation and promotes the non-amyloidogenic route of APP processing, thus preventing the formation of Aβ and its subsequent accumulation. Taken together, these results suggest that EGCG may be a suitable candidate in the search for potential therapeutic compounds for neurodegenerative disorders involving inflammation and oxidative stress, including Alzheimer's disease.

Complement C3a receptor antagonist alleviates tau pathology and ameliorates cognitive deficits in P301S mice

Human tauopathies, including Alzheimer's disease (AD), are a major class of neurodegenerative diseases characterized by intracellular deposition of pathological hyperphosphorylated forms of Tau protein. Complement system is composed of many proteins, which form a complex regulatory network to modulate the immune activity in the brain. Emerging studies have demonstrated a critical role of complement C3a receptor (C3aR) in the development of tauopathy and AD. The underlying mechanisms by which C3aR activation mediates tau hyperphosphorylation in tauopathies, however, remains largely unknown. Here, we observed that the expression of C3aR is upregulated in the brains of P301S mice - a mouse model of tauopathy and AD. Pharmacologic blockade of C3aR ameliorates synaptic integrity and reduced tau hyperphosphorylation in P301S mice. Besides, the administration of C3aR antagonist (C3aRA: SB 290157) improved spatial memory as tested in the Morris water maze. Moreover, C3a receptor antagonist inhibited tau hyperphosphorylation by regulating p35/CDK5 signaling. In summary, results suggest that the C3aR plays an essential role in the accumulation of hyperphosphorylated Tau and behavioral deficits in P301S mice. C3aR could be a feasible therapeutic target for the treatment of tauopathy disorders, including AD.

Continuous wave 670nm LED light therapy improves short‐ and long‐term object recognition, locomotion, and reduces phosphorylated tau burden in 3xTgAD mice

AbstractBackgroundPhotobiomodulation (PBM) therapy uses 620‐1100nm red to near‐infrared light to modulate biological processes including neuroinflammation, amyloid and tau oligomerization, and apoptosis. We have shown that 670nm light therapy reduces synaptic vulnerability to amyloid‐β oligomers in wild‐type (WT) mice and reduces tau oligomerization in mouse models of tauopathy. Here we sought to determine if 670nm light therapy could rescue cognitive and motor dysfunction and reduce tau hyperphosphorylation in 14‐to‐18‐month‐old 3xTgAD mice.Method14‐to‐18‐month‐old 3xTgAD mice were treated with continuous‐wave 670nm LED light applied directly to the head for 90s per day, 5 days per week for 4 weeks. 3xTgAD sham and WT controls were held under the LED device with the light turned off for the same amount of time. During the fourth week of treatment, spontaneous locomotor behavior was measured by placing animals in an empty chamber for 10 minutes using ANY‐maze software to track mobility data. Animals were then tested for working memory in the Y maze spontaneous alternation task and short‐and long‐term memory in the novel object recognition task. At the completion of behavioral testing on treatment day 20, brains were collected for western blot analysis of total tau and phospho‐tau (pTau).ResultLight‐treated 3xTgAD mice showed increased distance traveled compared to sham (17.43 ± 3.46 vs. 9.97 ± 3.03, one‐way ANOVA p = 0.03), and decreased immobile episodes (4.50 ± 1.92 vs 10.00 ± 1.83, one‐way ANOVA p = 0.02) in the spontaneous locomotor activity test. Light‐treated animals also showed significant object recognition at 2 hours (DI 32.75 ± 7.71, one sample t‐test p<0.001) and 24 hours (DI 44.14 ± 15.73, one sample t‐test p = 0.001) post‐training. Light treatment also reduced the ratio of hippocampal pTau/Tau in 3xTg AD mice as compared to sham (0.11 ± 0.05 vs. 0.32 ± 0.13, one‐way ANOVA p = 0.04).ConclusionHere we show rescue of locomotor behavior and cognitive dysfunction, and reduction of Tau phosphorylation in the hippocampus of 3xTgAD mice using a non‐invasive transcranial treatment with 670nm LED light. Our data suggest that treatment with 670nm red light could significantly improve cognitive function in AD patients and reduce hyperphosphorylation of tau thus possibly preventing further neurodegeneration.

Chinese medicine monomers in the treatment of Alzheimer’s disease: Some preclinical findings

AbstractBackgroundMost of the FDA approved drugs for AD are symptom driven and effects are limited. Because AD is a complex disease involving multiple pathological changes, such as senile plaques formed by amyloid‐β (Aβ) deposition, neurofibrillary tangles caused by tau hyperphosphorylation, microglia‐evoked neuroinflammation, synaptic degeneration, and blood‐brain barrier (BBB) disruption. While the current anti‐dementia drugs are mostly single targets, Chinese medicines have great development potential considering their multi‐target anti‐dementia components.MethodSeveral Chinese medicine monomers, including cryptotanshinone (CTS), pterostilbene (PTE), Ginsenoside Compound K (GCK), and glabridin (Gla) were selected to test their safety and efficacy in AD cell models, and to further explore their possible molecular mechanisms and target of action. Aβ42 oligomers (AβO) were used to establish AD cell models. The cytotoxicity of AβO as well as protective effects of Chinese medicine monomers on cell models were evaluated using the MTT assay. The molecular mechanisms and pathways were tested using qRT‐PCR, ELISA, Western blot and immunofluorescence.ResultAβO induced cell injury, apoptosis, and generation of intracellular reactive oxygen species (ROS). In AβO‐induced cell models, CTS significantly reduced tau hyperphosphorylation at Ser202, Ser404, Thr181, and Thr231, and increased the levels of PSD95 and synaptophysin; PTE attenuated cell injury, apoptosis, and ROS generation; GCK diminished inflammatory cytokine production; Gla attenuated cell injury (figure1). Further study found that their mechanisms of action include PI3K/Akt/GSK3β pathway (figure2), BBB permeability and tight junction scaffold protein (figure3), as well as NF‐kB pathway via LRP1 activation (figure4), respectively.ConclusionThese results provides rational basis for the therapeutic application of Chinese medicine monomers in the treatment of AD, and support further evaluation of these multi‐target action potential in AD treatment.

The Protective Effect of Mangiferin on Formaldehyde-Induced HT22 Cell Damage and Cognitive Impairment.

Formaldehyde (FA) has been found to induce major Alzheimer's disease (AD)-like features including cognitive impairment, Aβ deposition, and Tau hyperphosphorylation, suggesting that it may play a significant role in the initiation and progression of AD. Therefore, elucidating the mechanism underlying FA-induced neurotoxicity is crucial for exploring more comprehensive approaches to delay or prevent the development of AD. Mangiferin (MGF) is a natural C-glucosyl-xanthone with promising neuroprotective effects, and is considered to have potential in the treatment of AD. The present study was designed to characterize the effects and mechanisms by which MGF protects against FA-induced neurotoxicity. The results in murine hippocampal cells (HT22) revealed that co-treatment with MGF significantly decreased FA-induced cytotoxicity and inhibited Tau hyperphosphorylation in a dose-dependent manner. It was further found that these protective effects were achieved by attenuating FA-induced endoplasmic reticulum stress (ERS), as indicated by the inhibition of the ERS markers, GRP78 and CHOP, and downstream Tau-associated kinases (GSK-3β and CaMKII) expression. In addition, MGF markedly inhibited FA-induced oxidative damage, including Ca2+ overload, ROS generation, and mitochondrial dysfunction, all of which are associated with ERS. Further studies showed that the intragastric administration of 40 mg/kg/day MGF for 6 weeks significantly improved spatial learning ability and long-term memory in C57/BL6 mice with FA-induced cognitive impairment by reducing Tau hyperphosphorylation and the expression of GRP78, GSK-3β, and CaMKII in the brains. Taken together, these findings provide the first evidence that MGF exerts a significant neuroprotective effect against FA-induced damage and ameliorates mice cognitive impairment, the possible underlying mechanisms of which are expected to provide a novel basis for the treatment of AD and diseases caused by FA pollution.

An inhibitor with GSK3β and DYRK1A dual inhibitory properties reduces Tau hyperphosphorylation and ameliorates disease in models of Alzheimer's disease

Since Alzheimer's disease (AD) is a complex and multifactorial neuropathology, the discovery of multi-targeted inhibitors has gradually demonstrated greater therapeutic potential. Neurofibrillary tangles (NFTs), the main neuropathologic hallmarks of AD, are mainly associated with hyperphosphorylation of the microtubule-associated protein Tau. The overexpression of GSK3β and DYRK1A has been recognized as an important contributor to hyperphosphorylation of Tau, leading to the strategy of using dual-targets inhibitors for the treatment of this disorder. ZDWX-12 and ZDWX-25, as harmine derivatives, were found good inhibition on dual targets in our previous study. Here, we firstly evaluated the inhibition effect of Tau hyperphosphorylation using two compounds by HEK293-Tau P301L cell-based model and okadaic acid (OKA)-induced mouse model. We found that ZDWX-25 was more effective than ZDWX-12. Then, based on comprehensively investigations on ZDWX-25 in vitro and in vivo, 1) the capability of ZDWX-25 to show a reduction in phosphorylation of multiple Tau epitopes in OKA-induced neurodegeneration cell models, and 2) the effect of reduction on NFTs by 3xTg-AD mouse model under administration of ZDWX-25, an orally bioavailable, brain-penetrant dual-targets inhibitor with low toxicity. Our data highlight that ZDWX-25 is a promising drug for treating AD.

Passive immunization inhibits tau phosphorylation and improves recognition learning and memory in 3xTg-AD mice

Tau pathology is essential in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Tau immunotherapy aimed at reducing the progression of tau pathology provides a potential therapeutic strategy for treating these diseases. By screening monoclonal antibodies 43D, 63B, 39E10, and 77G7 that recognize epitopes ranging from tau's N-terminus to C-terminus, we found the 77G7, which targets the microtubule-binding domain promoted tau clearance in a dose-dependent manner by entering neuronal cells in vitro. Intra-cerebroventricular injection of 77G7 antibody reduced tau levels in the wild-type FVB mouse brain. Without influencing the levels of detergent-insoluble and aggregated tau, intravenous injection of 77G7 reduced tau hyperphosphorylation in the brain and improved novel object recognition but not spatial learning and memory in 15–18-month-old 3xTg-AD mice. These studies suggest that epitopes recognized by tau antibodies are crucial for the efficacy of immunotherapy. Immunization with antibody 77G7 provides a novel potential opportunity for tau-directed immunotherapy of AD and related tauopathies.

MicroRNAs as Possible Biomarkers for Diagnosis and Therapy of Alzheimer’s Disease by Regulating the Abnormal Expression of Genes Related to Tau

Alzheimer’s disease (AD), the most common dementia with the symptom of deterioration of memory and cognitive functions, becomes one of the prevalent threats globally. Tau hyperphosphorylation is one of major risk factors of AD. At present, there is no effective treatment or quick diagnostic methods for the pre-clinical stage of this disease. MicroRNAs (miRNAs) are small (20-25bp) non-coding, double stranded RNA molecule. They mainly regulate gene expression during the post-transcription by binding to the 3-’UTR of the mRNA then stop translation. Unlike other biomarkers using for Alzheimer’s disease, miRNAs are stable and widely found in body fluids such as serum, tissues, and Cerebrospinal fluid (CSF) and one miRNA can regulate multiple genes. As a result, they are potentially used as diagnosis or therapeutic biomarkers for many diseases including Alzheimer’s disease. Currently, this field that using miRNAs as biomarkers for diagnosis and treatment has been rapidly developed. To examine the mechanism and function of miRNAs and potential in AD, this review summarizes current diagnostic and therapeutic techniques and comparing several microRNAs that especially regulating tau toxicity as practicable diagnostic biomarkers and treatment agents. It is likely to detect different stages of Alzheimer’s disease and reduce Tau hyperphosphorylation if this field of miRNA as biomarkers carries forward.

Metformin Attenuates Tau Pathology in Tau-Seeded PS19 Mice

Accumulation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau is a histopathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Growing evidence demonstrated that tau pathology in AD spreads in a prion-like manner. Previous studies showed that metformin might have a positive effect on cognition. However, the underlying mechanisms are still unknown. Therefore, the present study aimed to investigate the effects of metformin on tau propagation. Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of PS19 mice. Metformin was administrated through drinking water for four months, and we observed tau spreading in the brain of tau-seeded PS19 mice. Metformin inhibited the spreading of tau pathology in the ipsilateral hemisphere, attenuated tau pathology in the contralateral hemisphere, and reduced the hyperphosphorylation of tau at Ser202/Thr205, Thr231, and Ser422 sites in the soluble fraction and Ser202/Thr205, Ser262, Thr396, Thr231, and Ser422 sites in the insoluble fraction of tau-seeded PS19 mice brains. Metformin did not affect tau kinases or phosphatase 2A protein levels but reduced mTORC1 protein levels. Additionally, metformin reduced learning and memory deficits of the tau-seeded PS19 mice. These findings indicate that metformin reduced tau hyperphosphorylation, attenuated tau pathology in tau-seeded PS19 mice, and improved learning and memory deficits. These findings highlight the potential mechanisms underlying the beneficial effects of metformin on cognition, implying that metformin could be a promising drug for the prevention and early treatment of AD.

Analog of kynurenic acid decreases tau pathology by modulating astrogliosis in rat model for tauopathy.

Kynurenines have immunomodulatory and neuroactive properties and can influence the central nervous system. Previous studies showed the involvement of the kynurenines in the pathogenesis and progression of neurodegenerative disease. In neurodegenerative disorders, including tauopathies, the tryptophan metabolism is shifted toward neurotoxic agents and the reduction of neuroprotectant products. Astrocyte-derived kynurenic acid serves as a neuroprotectant. However, systemic administration of kynurenic acid is not effective because of low permeability across the blood-brain barrier (BBB). We used a kynurenic acid analog with similar biological activity but higher brain permeability to overcome BBB limitations. In the present study, we used amide derivate of kynurenic acid N-(2-N, N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamid (KYNA-1). We administered KYNA-1 for three months to tau transgenic rats SHR-24 and analyzed the effect on tau pathology and activation of glial cells. Primary glial cell cultures were applied to identify the mechanism of the KYNA-1 effect. KYNA-1 was not toxic to rats after chronic three-month administration. When chronically administered, KYNA-1 reduced hyperphosphorylation of insoluble tau in the brain of transgenic rats. Noteworthily, the plasma total tau was also reduced. We determined that the effect of KYNA-1 on tau pathology was induced through the modulation of glial activation. KYNA-1 inhibited LPS induced activation of astrocytes and induced transformation of microglia to M2 phenotype. We identified that the administration of KYNA-1 reduced tau hyperphosphorylation and neuroinflammation. KYNA-1 may serve as a promising treatment for tauopathies.

Cryptotanshinone Attenuates Amyloid-β42-induced Tau Phosphorylation by Regulating PI3K/Akt/GSK3β Pathway in HT22 Cells.

The pathological characteristics of Alzheimer's disease (AD) include formation of senile plaques resulting from amyloid-β (Aβ) deposition and neurofibrillary tangles caused by tau hyperphosphorylation. Reducing tau hyperphosphorylation is crucial for treatment of AD. Network pharmacology analysis showed that CTS may reduce tau hyperphosphorylation by regulating the phosphatidylinositol 3 kinases/protein kinase B/ glycogen synthase kinase-3β (PI3K/Akt/GSK3β) pathway. We investigated the ability of cryptotanshinone (CTS) to reduce Aβ-induced tau hyperphosphorylation and characterized the underlying mechanisms. Amyloid-β42 oligomers (AβO) were used to establish an AD model in HT22 cells. The expression levels of tau and related proteins in PI3K/Akt/GSK3β pathway were measured using western blot and immunofluorescence staining. The above-mentioned proteins were then evaluated in an okadaic acid (OKA)-induced AD cell model to verify the results. Synapse-associated proteins including post-synaptic density protein-95 (PSD95) and synaptophysin were also evaluated. We found that CTS significantly reduced tau hyperphosphorylation at Ser202, Ser404, Thr181, and Thr231 in AβO- and OKA-induced cell models. Moreover, we also found that CTS reversed AβO-induced reductions in the levels of PSD95 and synaptophysin. We used LY294002 to block PI3K and the results showed that CTS exerted neuroprotective effects through regulation of the PI3K/Akt/GSK3β signaling pathway. In summary, we showed for the first time that CTS inhibited AD-related tau hyperphosphorylation and reduced the effects of AβO on the expression levels of PSD95 and synaptophysin via the PI3K/Akt/GSK3β pathway in HT22 cells.