Decreased Tau Hyperphosphorylation Research Articles

Dendrobium nobile Lindl. alkaloid decreases Tau hyperphosphorylation via regulating PI3K/Akt/GSK-3β pathway in vitro and in vivo

Ethnopharmacological relevantDendrobium is a traditional and precious Chinese medicinal herb. The Compendium of Materia Medica describes its effects as “benefiting intelligence and dispelling shock, lightning the body and extending life”. Dendrobium nobile Lindl. is a precious variety of Dendrobium. Our previous data showed Dendrobium nobile Lindl. alkaloid (DNLA) has significant neuroprotective effects and can improve cognitive dysfunction. However, the specific effects and mechanisms of action of its main active component, DNLA, on cognitive dysfunction caused by Tau hyperphosphorylation, are still unclear. Aim of the researchThis study aimed to determine the effects of DNLA on phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3β (GSK-3β) pathway, thus to explore the mechanisms of DNLA to inhibit Tau hyperphosphorylation. Materials and methodsWe used wortmannin (WM) and GF-109203X (GFX)-induced hyperphosphorylation of Tau in N2a cells and rats to detect the protective mechanism of DNLA in vivo and in vitro. In vitro, the effect of modeling method on Tau hyperphosphorylation was screened and verified by Western Blotting (WB), and the regulation of Tau hyperphosphorylation and PI3K/Akt/GSK-3β pathway by different concentrations of DNLA was detected by WB. In vivo, MWM was used to detect the effect of DNLA on model rats, and then Nissl staining was used to detect the loss of neurons. Finally, WB was used to detect the regulation of Tau hyperphosphorylation and PI3K/Akt/GSK-3β pathway by different concentrations of DNLA. ResultsDNLA could rescue the abnormal PI3K/Akt/GSK-3β pathway and reverse the hyperphosphorylation of Tau induced by WM and GFX in N2a cells. Furthermore, DNLA improved the learning and memory of WM and GFX-induced model rats. Moreover, DNLA regulated PI3K/Akt/GSK-3β pathway and reduced the p-Tau and neuronal damage in the hippocampus of model rats. ConclusionDNLA may be a promising candidate for reducing hyperphosphorylation of Tau.

AZP2006, a New Promising Treatment for Progressive Supranuclear Palsy patients. Phase 2a Study Assessing Tolerability, Safety and Pharmacokinetics. Effect on Biomarkers and Clinical Readouts

AbstractBackgroundProgressive Supranuclear Palsy (PSP) is a rare progressive, fatal neurodegenerative 4‐repeat tauopathy. AZP2006 (INN: Ezeprogind) is a first‐in‐class disease‐modifying oral small molecule acting via its strong binding to the complex Progranulin (PGRN) / Prosaposin (PSAP), able to increase the circulating contents of PGRN (plasma and brain) in non‐clinical models. Preclinically, AZP2006 promotes neuron survival, synaptic function, decreases Tau hyperphosphorylation and reduces neuroinflammation (in vitro and in vivo models of Alzheimer’s disease, PSP and Parkinson’s disease). In healthy volunteers Phase 1 studies, AZP2006 was well tolerated with a good safety profile.MethodAZP2006 safety, tolerability and pharmacokinetic profiles in plasma, whole blood, and CSF were investigated in a randomized, double‐blind, placebo‐controlled, parallel group study comparing 2 doses of AZP2006 (60 mg once daily during the 12‐week treatment period and 80 mg once daily for 10 days followed by 50 mg once daily) with placebo in 36 men and women aged ≥40 years and ≤80 years diagnosed with probable or possible PSP. Patients were observed for an additional 12‐week follow‐up period (NCT04008355).In secondary objectives, CSF biomarkers including PGRN for the target engagement and markers of neurodegeneration (NfL, phospho‐tau T181) as well as markers of neuroinflammation (sTREM2, interleukins, etc.) were quantified. In addition, exploratory efficacy objectives evaluating clinical endpoints (PSP‐RS total, PSP Gait, PSP Ocular, CGI‐ds, Schwab and England ADL) were investigated.ResultAZP2006 was safe and well tolerated; no related SAEs were reported. PK profile confirmed the long AZP2006 half‐life (as predicted in a prior popPK model). High brain penetrance was observed and AZP2006 CSF expected levels were achieved. In addition, the target engagement was confirmed by significant increase (vs baseline) of PGRN plasma levels. A PD‐PK analysis is planned.ConclusionAZP2006 treatment showed promising effects after a 3‐month‐treatment. Considering these promising results, an open‐labelled extension (OLE) was started (60 mg daily) in France. In addition, a larger Phase 2b/3 study in PSP patients testing AZP2006 efficacy over 12‐month‐treatment is under preparation.

Qingxin Kaiqiao Fang decreases Tau hyperphosphorylation in Alzheimer's disease via the PI3K/Akt/GSK3β pathway in vitro and in vivo

Ethnopharmacological relevanceAlzheimer's disease (AD) belongs to the category of “senile dementia” in traditional Chinese medicine. AD is associated with brain emptiness or collaterals blocked by phlegm-heat. “Fumanjian” from Jingyue Quanshu treats dementia by promoting qi circulation, alleviating depression, eliminating turbidity, cultivating positivity, and dispelling evil spirits. Qingxin Kaiqiao Fang (QKF), derived from Fumanjian, is effective in treating AD owing to previously mentioned clinical effects. Elucidating the mechanism(s) of action of QKF on AD associated with phlegm-heat may be beneficial for therapeutic management; however, further research is needed. Aim of the studyThis study aimed to determine the role of the PI3K/Akt pathway in AD, especially the specific effector protein involved, and explore the efficacy of QKF in treating AD by modulating the PI3K/Akt signal. Materials and methodsHigh-performance liquid chromatography-Q-orbitrap-mass spectrometry was used to analyze the chemical components of QKF. Subsequently, APP/PS1 double-transgenic mice were used for behavioral tests, and hematoxylin-eosin and Nissl staining were used to assess the neuroprotective and cognitive effects of QKF. Cerebrospinal fluid pharmacology was used in in vitro validation, and Aβ25-35 was used to induce PC12 cells to establish the AD cell model. Various methods, including immunohistochemistry, Western blotting, quantitative real-time polymerase chain reaction, morphological assay, cell counting kit-8(CCK-8) assay, and terminal deoxynucleotide transferase (TdT)-mediated dUTP nick-end labeling (TUNEL)staining, were used to evaluate the effect of QKF on Tau hyperphosphorylation and anti-apoptosis. These methods also assessed the influence of QKF on the PI3K/Akt/GSK3β pathway involving the mRNA and protein expressions. Finally, the inhibitor - LY294002 was used for reverse validation. ResultsWe identified 295 chemical components in the water extract of QKF.QKF improved spatial cognition and learning memory in APP/PS1 mice, protected PC12 cell morphology, improved cell survival, reduced Aβ25-35-induced apoptosis, and inhibited the hyperphosphorylation of Tau protein via the PI3k/Akt/GSK3β signaling pathway. Furthermore, this protective effect of QKF was reduced by LY294002 in vitro. ConclusionsQKF can improve spatial cognition, learning, and memory abilities in APP/PS1 mice and protect PC12 cells. Decreasing the Tau hyperphosphorylation in AD exhibits curative efficacy on AD via the PI3K/Akt/GSK3β pathway in vitro and in vivo.

Reduction of kinesin I heavy chain decreases tau hyperphosphorylation, aggregation, and memory impairment in Alzheimer's disease and tauopathy models.

Many neurodegenerative diseases, such as Alzheimer's disease (AD) and frontotemporal dementia with Parkinsonism linked to chromosome 17, are characterized by tau pathology. Numerous motor proteins, many of which are involved in synaptic transmission, mediate transport in neurons. Dysfunction in motor protein-mediated neuronal transport mechanisms occurs in several neurodegenerative disorders but remains understudied in AD. Kinesins are the most important molecular motor proteins required for microtubule-dependent transport in neurons, and kinesin-1 is crucial for neuronal transport among all kinesins. Although kinesin-1 is required for normal neuronal functions, the dysfunction of these motor domains leading to neurodegenerative diseases is not fully understood. Here, we reported that the kinesin-I heavy chain (KIF5B), a key molecular motor protein, is involved in tau homeostasis in AD cells and animal models. We found that the levels of KIF5B in P301S tau mice are high. We also found that the knockdown and knockout (KO) of KIFf5B significantly decreased the tau stability, and overexpression of KIF5B in KIF5B-KO cells significantly increased the expression of phosphorylated and total tau levels. This suggested that KIF5B might prevent tau accumulation. By conducting experiments on P301S tau mice, we showed that partially reducing KIF5B levels can reduce hyperphosphorylation of the human tau protein, formation of insoluble aggregates, and memory impairment. Collectively, our results suggested that decreasing KIF5B levels is sufficient to prevent and/or slow down abnormal tau behavior of AD and other tauopathies.

Monascus purpureus Fermented Product Ameliorates Learning and Memory Impairment in the Amyloid Precursor Protein Transgenic J20 Mouse Model of Alzheimer’s Disease

Evidence suggests that various hallmarks such as amyloid overproduction, tau dysfunction, insulin resistance/diabetic mechanisms, and neuroinflammation are associated with Alzheimer’s disease (AD). This study investigated the bioactive functions of ankaflavin (AK) and monascin (MS) in the fermented product of Monascus purpureus and found their abilities to ameliorate AD by modifying several important pathogenic factors including improved cognitive function, reversed behavioral deficits, reduced hippocampal β-amyloid peptide (Aβ) burden, decreased tau hyper-phosphorylation, and reduced neuroinflammation in the J20 mouse model of AD compared to wild type. Monascus purpureus fermented product (MPFP) was suggested to act as a peroxisome proliferator-activated receptor (PPAR)-γ agonist and it was compared against the action of a well-known anti-diabetic PPAR-γ agonist rosiglitazone. MPFP could be a promising therapeutic strategy for disease modification in AD.

AZP2006/EZEPROGIND neuroprotective effect in age-related cognitive decline and Alzheimer's disease progression.

AZP2006/EZEPROGIND is a disease-modifying small molecule that is currently in clinical development for the treatment of Progressive Supranuclear Palsy (PSP). Here we investigated its neuroprotective effect on in vitro and in vivo models of Alzheimer's disease (AD). We showed that AZP2006/EZEPROGIND neuroprotective action is mediated by Progranulin (PGRN) and correlated with a reduction of neuroinflammation. Primary rat cortical neurons cultured with microglia were injured with Aβ1-42 oligomers. We investigated the effect of AZP2006/EZEPROGIND on neuronal survival and neurite network (MAP2), synapses (PSD95/SYN), pTau (AT100), microglia activation (OX-41), neuroinflammation (IL-1β and IL-6) and PGRN levels. The PGRN mediated effect of AZP2006/EZEPROGIND was assessed by blocking Ab anti PGRN and siRNA for PGRN and/or Prosaposin (PSAP). AZP2006/EZEPROGIND (3 mg/kg/day) was also orally administered to the Senescence Accelerated Mouse-Prone 8 (SAMP8) mice, a spontaneous animal model of accelerated aging, from the age of 2, 4 or 6 months to 10 months. Learning and memory deficits were evaluated by Y-Maze Test and by Passive Avoidance Test. PGRN levels and of biochemical markers of oxidative stress (LPO), pTau (T181), Aβ1-42 , proinflammatory cytokines (IL-1β and IL-6), neuronal (NeuN) and microglial (Iba1) markers were studied by ELISA and IHC. In vitro, nM concentrations of AZP2006/EZEPROGIND significantly increased the neuron survival, the neurite network and the number of synapses. The incubation with blocking Ab anti PGRN and siRNA for PGRN and/or PSAP abolished these effects. Also, AZP2006/EZEPROGIND significantly decreased Tau hyperphosphorylation and reduced the neuroinflammation. The chronic treatment with AZP2006/EZEPROGIND significantly increased the Spontaneous Alternation in the Y-Maze Test and the Step-through Latency in the Passive Avoidance Test. We showed that AZP2006/EZEPROGIND was able to protect neurons, enhance synaptic function, decrease the hyperphosphorylation of Tau and reduce the neuroinflammation via PGRN. The chronic oral treatment was able to prevent, protect and restore the aged-related cognitive decline in the SAMP8 mice. We postulate that neuroprotective properties of AZP2006/EZEPROGIND not only could delay the progression of AD but also has the potential to reverse aged-related cognitive damages.

The Link Between Diabetes Mellitus and Tau Hyperphosphorylation: Implications for Risk of Alzheimer's Disease.

Diabetes mellitus (DM) is characterized by hyperglycemia caused by a lack of insulin, insulin resistance, or both. It is associated with the development of secondary complications resulting in several comorbidities. Recent studies have revealed an increased risk of developing cognitive dysfunction or dementia in diabetes patients. Diabetes mellitus is considered a risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD). There is increasing evidence to support a link between DM and AD. Studies have shown the dysfunction of insulin signaling in the brain, resulting in increased tau protein phosphorylation (hyperphosphorylation), a hallmark and biomarker of AD pathology, leading to accumulation of neurofibrillary tangles. In DM, the insulin dysfunction in the brain is reported to alter the glycogen synthase kinase-3β (GSK-3β) activity showing to enhance tau phosphorylation. In DM and AD, GSK-3β signaling has been involved in the physiological and pathological processes, respectively. This potentially explains why DM patients have an increased risk of developing AD with disease progression and aging.Interestingly, several in vivo studies with oral antidiabetic drugs and insulin treatment in DM have improved cognitive function and decreased tau hyperphosphorylation. This article will review the relationship between DM and AD as it relates to tau pathology. More understanding of the link between DM and AD could change the approach researchers and clinicians take toward both diseases, potentially leading to new treatments and preventative strategies in the future.

Effect of Endurance Exercise and MitoQ Intake on Tau Hyperphosphorylation, Oxidative Stress, Antioxidant Modulating Factors, Mitochondrial Function, and Cognitive Function in Alcl3-Induced Alzheimer’s Disease Animal Model

PURPOSE: This study aimed to investigate the effect of 8 weeks of endurance exercise and MitoQ intake on tau hyperphosphorylation, oxidative stress, antioxidant modulating factors, mitochondrial function, and cognitive function in an AlCl3-induced Alzheimer’s disease animal model.METHODS: For the experimental animals, 40 mg/kg of aluminum chloride (AlCl3) was diluted with physiological saline for 60 days and intraperitoneally injected to create an Alzheimer’s disease animal model. In addition, endurance exercise was performed at a speed of 12 m/min using a treadmill for laboratory animals for 8 weeks, and MitoQ was applied with a 100 μm concentration of negative water. The rats were randomly divided into five groups: a saline control group (NC, n=6), an AlCl3 injection group (AC, n=6), an AlCl3 injection and treadmill exercise group (AE, n=6), an AlCl3 injection and MitoQ group (AM, n=6), and an AlCl3 injection and treadmill exercise and MitoQ intake group (AEM, n=6). The SPSS program was used for statistical analyses. Differences between the groups in each variable were analyzed using the one-way ANOVA.RESULTS: Endurance exercise and MitoQ intake for 8 weeks showed positive results in cognitive function and decreased tau hyperphosphorylation in the animal model with Alzheimer’s disease. In addition, they reduced oxidative stress (4-HNE, MDA) and had a positive effect on antioxidant indicators (catalase, SOD-1, SOD-2). Finally, they exhibited a positive effect on factors related to mitochondrial function (PGC-1, Tfam).CONCLUSIONS: Eight weeks of endurance exercise and MitoQ intake are thought to have a positive effect in alleviating Alzheimer’s disease in terms of improving cognitive function through AlCl3 accumulation, tau hyperphosphorylation, oxidative stress, antioxidant modulating factors, and mitochondrial function.

Preventive electroacupuncture reduces cognitive deficits in a rat model of D-galactose-induced aging.

Acupuncture can reduce cognitive deficits in Alzheimer's disease. However, whether electroacupuncture can prevent or alleviate the cognitive deficits in animal models of aging remains poorly understood. Studies have shown that disordered epigenetic modifications play a critical role in age-related cognitive decline. Therefore, we hypothesized that preventive electroacupuncture might improve cognitive functions during aging by regulating epigenetic modifications. A rat model of aging was produced by intraperitoneal injection of 120 mg/kg D-galactose for 8 weeks. Baihui and Shenshu acupoints were stimulated by electroacupuncture for 8 weeks from the first day of D-galactose administration. Preventive electroacupuncture alleviated memory impairment, decreased tau hyperphosphorylation, and reduced glycogen synthase kinase-3β protein and mRNA expression levels in the brainstem dorsal raphe nucleus, where intracellular neurofibrillary tangle lesions first occur. In addition, the DNA methylation level in the promoter region of the glycogen synthase kinase-3β gene was increased. The effects of preventive electroacupuncture were stronger than those of preventive acupuncture. Intraperitoneal injection of 0.4 mg/kg 5-aza-2'-deoxycytidine, an inhibitor of DNA methyltransferase that blocks epigenetic modifications, antagonized the effects of preventive electroacupuncture. Our results suggest that preventive electroacupuncture treatment alleviates cognitive impairment in aging rats probably by affecting the epigenetic modification of the glycogen synthase kinase-3β gene in the dorsal raphe nucleus. This study was approved by the Animal Ethics Committee of Hubei University of Chinese Medicine, China (approval No. HUCMS201712001) on November 28, 2017.

Oral benfotiamine reverts cognitive deficit and increase thiamine diphosphate levels in the brain of a rat model of neurodegeneration.

It is well known that patients with Alzheimer's disease (AD) have imbalances in blood thiamine concentrations and lower activity of thiamine-dependent enzymes. Benfotiamine, a more bioavailable thiamine analog, has been proposed as an alternative to counteract these changes related to thiamine metabolism. Thus, our study aimed to analyze the effects of benfotiamine supplementation on brain thiamine absorption, as well as on parameters related to neuronal energy metabolism and disease progression in an experimental model of sporadic AD induced by intracerebroventricular injection of streptozotocin (STZ) in rats. The supplementation with 150 mg/kg of benfotiamine for 30 days increased the concentrations of thiamine diphosphate in the hippocampus and entorhinal cortex. This led to an improvement in mitochondria enzymes and insulin signaling pathway, with inactivation of GSK3α/β and ERK1/2, which are two tau-kinases related to the progression of AD, which could decrease tau hyperphosphorylation and apoptosis signaling. Besides, we observed an increased amount of Glun2b subunit of NMDA receptors, decreased inflammation, and improvement of cognitive deficit. Together, these results suggest that benfotiamine could be a potential therapeutic approach in the treatment of sporadic AD.

SCR-1693 inhibits tau phosphorylation and improves insulin resistance associated cognitive deficits

Except for few symptoms-improved drugs for Alzheimer's disease (AD), no disease-modified drug has been developed, especially for AD in type 2 diabetes mellitus (T2DM). SCR-1693, a disease-mortified candidate for AD, which is now in Phase I clinical study in China, improves Aβ25–35-impaired cognitive function in rodent's models. Here we report the effect of SCR-1693 on regulation of tau phosphorylation and insulin resistance associated cognition, and illustrate its underlying mechanism. We found that in intracerebroventricular injection of streptozotcin (STZ) rats, oral administration of SCR-1693 dose-dependently improved the learning and memory in Morris water maze test, decreased tau hyperphosphorylation, astrogliosis and postsynaptic protein loss in hippocampus. In Neura-2a cells with stable transfection of full-length human tau (Neura-2a-tau), treatment of SCR-1693 concentration-dependently enhanced the activation of protein phosphatase (PP1) and protein phosphatase 2A (PP2A), decreased cellular tau phosphorylation, and increased insulin-induced cellular signaling to reverse insulin resistance. Pre-treatment with the inhibitor of PP1 and PP2A inhibited the effect of SCR-1693 on both of tau phosphorylation and insulin signaling in Neura-2a-tau cells. All data suggest that an increase of activity of tau phosphatase was involved in the mechanism of SCR-1693 on the regulation of tau phosphorylation and insulin signaling, and SCR-1693 is considerable candidate for insulin resistance associated sporadic AD.

Identification of crizotinib derivatives as potent SHIP2 inhibitors for the treatment of Alzheimer's disease

SH2 domain-containing inositol 5′-phosphatase 2 (SHIP2) is a lipid phosphatase that produce phosphatidylinositol 3,4-bisphosphate (PI(3,4)P2) from phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P3), and is involved in many diseases such as neurodegenerative diseases. A recent report demonstrating that SHIP2 inhibition decreased tau hyperphosphorylation induced by amyloid β and rescued memory impairment in a transgenic Alzheimer's disease mouse model indicates SHIP2 can be a promising therapeutic target for Alzheimer's disease. In the present study, we have developed novel, potent SHIP2 inhibitors by extensive structural elaboration of crizotinib discovered from a high-throughput screening. Our representative compound 43 potently inhibited SHIP2 activity as well as GSK3β activation in HT22 neuronal cells. It was also shown that 43 has favorable physicochemical properties, especially high brain penetration. Considering SHIP2 is one of key signal mediators for tau hyperphosphorylation, our potent SHIP2 inhibitor 43 may function as a promising lead compound for the treatment of Alzheimer's disease.

Cornel Iridoid Glycoside Inhibits Tau Hyperphosphorylation via Regulating Cross-Talk Between GSK-3β and PP2A Signaling.

Neurofibrillary pathology contributes to neuronal dysfunction and correlates with the clinical progression of Alzheimer’s disease (AD). Tau phosphorylation is mainly regulated by a balance of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) activities. Cornel iridoid glycoside (CIG) is a main component extracted from Cornus officinalis. The purpose of this study was to investigate the effects of CIG on GSK-3β and PP2A, thus to explore the mechanisms of CIG to inhibit tau hyperphosphorylation. The rat model of tau hyperphosphorylation was established by intraventricular injection of wortmannin and GF-109203X (GFX) to activate GSK-3β. The results showed that intragastrical administration of CIG inhibited tau hyperphosphorylation in the brain of rats induced by wortmannin/GFX. The results in vivo and in vitro exhibited that CIG inhibited tau hyperphosphorylation and GSK-3β over-activation. In the mechanism of action, CIG’s attenuating GSK-3β activity was found to be dependent on PI3K/AKT signaling pathway. PP2A catalytic C subunit (PP2Ac) siRNA abrogated the effect of CIG on PI3K/AKT/GSK-3β. Additionally and crucially, we also found that CIG inhibited the demethylation of PP2Ac at Leu309 in vivo and in vitro. It enhanced PP2A activity, decreased tau hyperphosphorylation, and protected cell morphology in okadaic acid (OA)-induced cell model in vitro. PP2Ac siRNA abated the inhibitory effect of CIG on tau hyperphosphorylation. Moreover, CIG inhibited protein phosphatase methylesterase-1 (PME-1) and demethylation of PP2Ac, enhanced PP2A activity, and decreased tau hyperphosphorylation in PME-1-transfectd cells. Taken together, CIG inhibited GSK-3β activity via promoting P13K/AKT and PP2A signaling pathways. In addition, CIG also elevated PP2A activity via inhibiting PME-1-induced PP2Ac demethylation to inhibit GSK-3β activity, thus regulated the cross-talk between GSK-3β and PP2A signaling and consequently inhibited tau hyperphosphorylation. These results suggest that CIG may be a promising agent for AD therapy.

Effects of treadmill exercise on PI3K/AKT/GSK-3β pathway and tau protein in high-fat diet-fed rats.

[Purpose]This study aimed to clearly evaluate the effects of obesity on cerebral health. Thus, we induced obesity in rats using a long-term high-fat diet (HFD), then investigated its effects on insulin signaling and tau hyperphosphorylation. Additionally, we examined the effects of 8 weeks of treadmill exercise (TE) on insulin signaling and tau hyperphosphorylation.[Methods]Rats were separated into Normal Diet-Control, HFD-Control, and HFD-TE groups. TE loads were gradually increased. A passive avoidance test was used to evaluate cognitive function. Western blots were used to examine the abundance of the insulin receptor,phosphoinositide 3-kinase, protein kinase B, glycogen synthase kinase-3β, and tau proteins in the cerebral cortex; immunohistochemical analyses were used to examine the abundance of hyperphosphorylated tau in the cerebral cortex.[Results]TE in HFD-fed rats resulted in a significant lowering of bodyweight, abdominal visceral fat (AVF), the area under the glucose response curve, and the homeostatic model assessment-insulin resistance index, while it improved working memory. In addition, TE in HFD-fed rats decreased tau hyperphosphorylation and aggregation, while increasing insulin signaling-related protein activity.[Conclusion]After a 20-week HFD, the experimental animals exhibited increased weight, as well as impaired insulin resistance and blood glucose metabolism. HFD rats demonstrated abnormal insulin signaling and tau hyperphosphorylation in the cerebral cortex, as well as memory impairments that suggested reduced cerebral function. However, TE reduced AVF, improved insulin resistance in the peripheral tissues by increasing insulin sensitivity, and alleviated memory impairments by restoring insulin signaling and reducing tau hyperphosphorylation in the cerebral cortex.

Surfen and oxalyl surfen decrease tau hyperphosphorylation and mitigate neuron deficits in vivo in a zebrafish model of tauopathy

BackgroundTauopathies comprise a family of neurodegenerative disorders including Alzheimer’s disease for which there is an urgent and unmet need for disease-modifying treatments. Tauopathies are characterized by pathological tau hyperphosphorylation, which has been shown to correlate tightly with disease progression and memory loss in patients suffering from Alzheimer’s disease. We recently demonstrated an essential requirement for 3-O-sulfated heparan sulfate in pathological tau hyperphosphorylation in zebrafish, a prominent model organism for human drug discovery. Here, we investigated whether in vivo treatment with surfen or its derivatives oxalyl surfen and hemisurfen, small molecules with heparan sulfate antagonist properties, could mitigate tau hyperphosphorylation and neuronal deficits in a zebrafish model of tauopathies.ResultsIn vivo treatment of Tg[HuC::hTauP301L; DsRed] embryos for 2 days with surfen or oxalyl surfen significantly reduced the accumulation of the pThr181 tau phospho-epitope measured by ELISA by 30% and 51%, respectively. Western blot analysis also showed a significant decrease of pThr181 and pSer396/pSer404 in embryos treated with surfen or oxalyl surfen. Immunohistochemical analysis further confirmed that treatment with surfen or oxalyl surfen significantly decreased the AT8 tau epitope in spinal motoneurons. In addition, in vivo treatment of Tg[HuC::hTauP301L; DsRed] embryos with surfen or oxalyl surfen significantly rescued spinal motoneuron axon-branching defects and, as a likely consequence, the impaired stereotypical touch-evoked escape response. Importantly, treatment with hemisurfen, a surfen derivative devoid of heparan sulfate antagonist activity, does not affect tau hyperphosphorylation, nor neuronal or behavioural deficits in Tg[HuC::hTauP301L; DsRed] embryos.ConclusionOur findings demonstrate for the first time that surfen, a well-tolerated molecule in clinical settings, and its derivative, oxalyl surfen, could mitigate or delay neuronal defects in tauopathies, including Alzheimer’s disease.

Dexibuprofen prevents neurodegeneration and cognitive decline in APPswe/PS1dE9 through multiple signaling pathways

The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimer's disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI), in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimer's disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFα. Moreover, DXI reduced soluble β-amyloid (Aβ1-42) plaque deposition by decreasing APP, BACE1 and facilitating Aβ degradation by enhancing insulin-degrading enzyme. DXI also decreased TAU hyperphosphorylation inhibiting c-Abl/CABLES/p-CDK5 activation signal pathway and prevented spatial learning and memory impairment in transgenic mice. Therefore, chronic DXI treatment could constitute a potential AD-modifying drug, both restoring cognitive functions and reversing multiple brain neuropathological hallmarks.

Morin reverses neuropathological and cognitive impairments in APPswe/PS1dE9 mice by targeting multiple pathogenic mechanisms

Alzheimer's disease (AD) is the most common form of dementia worldwide, characterized by progressive cognitive impairment and multiple distinct neuropathological features. Currently, there are no available therapies to delay or block the disease progression. Thus, the disease-modifying therapies are urgent for this devastating disorder by simultaneously targeting multiple distinct pathological processes. Morin, a natural bioflavonoid, have been shown to be strongly neuroprotective in vitro and in vivo. In this study, we first investigated the disease-modifying effects of chronic morin administration on the neuropathological and cognitive impairments in APPswe/PS1dE9 double transgenic mice. Our results showed that chronic morin administration prevented spatial learning and memory deficits in the APPswe/PS1dE9 mice. Morin treatment in the APPswe/PS1dE9 mice markedly reduced cerebral Aβ production and Aβ plaque burden via promoting non-amyloidogenic APP processing pathway by increasing ADAM10 expression, inhibiting amyloidogenic APP processing pathway by decreased BACE1 and PS1 expression, and facilitating Aβ degradation by enhancing Aβ-degrading enzyme expression. In addition, we also found that morin treatment in the APPswe/PS1dE9 mice markedly decreased tau hyperphosphorylation via its inhibitory effect on CDK5 signal pathway. Furthermore, morin treatment in the APPswe/PS1dE9 mice markedly reduced the activated glial cells and increased the expression of synaptic markers. Collectively, our findings demonstrate that chronic morin treatment restores cognitive functions and reverses multiple distinct neuropathological AD-like hallmarks in the APPswe/PS1dE9 mice. This study provides novel insights into the neuroprotective actions and neurobiological mechanisms of morin against AD, suggesting that morin is a potently promising disease-modifying agent for treatment of AD.

Traditional Chinese Medicine Huannao Yicong Decoction Extract Decreases Tau Hyperphosphorylation in the Brain of Alzheimer's Disease Model Rats Induced by Aβ1-42.

Objective. Huannao Yicong Decoction (HYD, 还脑益聪方) has been shown to improve the learning and memory capabilities of Alzheimer's disease (AD) subjects. However, the underlying mechanism remains to be determined. Methods. Sixty Sprague-Dawley rats were divided equally and randomly into five different groups including control, positive control, and HYD granules of low dose, medium dose, and high dose by daily gavage. The sham-treated rats were also given the same volume of sterile water by gavage. Twelve SD rats were treated with the same amount of physiological saline. Twelve weeks later, learning and memory capabilities, Aβ content of the right brain and the expression of glycogen synthase kinase-3β (GSK-3β), total tau protein kinase (TTBK1), and cyclin-dependent kinase-5 (CDK-5) were tested. Results. Our results showed that high dose HYD treatment significantly improved the learning and memory capability of the AD rats and decreased the expression of TTBK1, GSK-3β, and CDK-5 in the hippocampal CA1 region. Conclusions. HYD treatment for 12 weeks significantly improved spatial learning and memory and effectively inhibited Aβ deposition, likely via reducing tau protein kinase expression and thus tau hyperphosphorylation and inflammatory injury. Taken together, these results suggest that HYD could be an effective treatment for AD.

Role of S-nitrosoglutathione mediated mechanisms in tau hyper-phosphorylation

Hyperphosphorylation and polymerization of microtubule-associated protein tau into paired helical filaments (PHFs) is one of the hallmarks of Alzheimer's disease (AD). Here we report that neuronal tau hyperphosphorylation under AD conditions is regulated by S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier molecule. In cultured rat cortical primary neurons, we observed that GSNO treatment decreased the β-amyloid (Aβ25–35)-induced pathological tau hyperphosphorylation (Ser396, Ser404, and Ser202/Thr205). The decreased tau hyperphosphorylation correlated with decreased activity of calpain and decreased p35 proteolysis into p25 and Cdk5 activation. GSNO treatment also attenuated the Aβ25–35-induced activation of GSK-3β which is known to play critical role in tau hyperphosphorylation in addition to Cdk5. Consistent with above studies using cultured neurons, we also observed that systemic GSNO treatment of transgenic mouse model of AD (APPSw/PS1dE9) attenuated calpain-mediated p35 proteolysis and Cdk5/GSK-3β activities as well as tau hyperphosphorylation. In addition, GSNO treatment provided neuro- and cognitive protection in APPSw/PS1dE9 mice. This study describing the GSNO-mediated regulation of tau hyperphosphorylation and cognitive function, for the first time, suggests for therapeutic potential of GSNO as neuro- and cognitive-protective agent for AD.

Magnesium protects cognitive functions and synaptic plasticity in streptozotocin-induced sporadic Alzheimer's model.

Alzheimer’s disease (AD) is characterized by profound synapse loss and impairments of learning and memory. Magnesium affects many biochemical mechanisms that are vital for neuronal properties and synaptic plasticity. Recent studies have demonstrated that the serum and brain magnesium levels are decreased in AD patients; however, the exact role of magnesium in AD pathogenesis remains unclear. Here, we found that the intraperitoneal administration of magnesium sulfate increased the brain magnesium levels and protected learning and memory capacities in streptozotocin-induced sporadic AD model rats. We also found that magnesium sulfate reversed impairments in long-term potentiation (LTP), dendritic abnormalities, and the impaired recruitment of synaptic proteins. Magnesium sulfate treatment also decreased tau hyperphosphorylation by increasing the inhibitory phosphorylation of GSK-3β at serine 9, thereby increasing the activity of Akt at Ser473 and PI3K at Tyr458/199, and improving insulin sensitivity. We conclude that magnesium treatment protects cognitive function and synaptic plasticity by inhibiting GSK-3β in sporadic AD model rats, which suggests a potential role for magnesium in AD therapy.