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Background: Both Alzheimer's disease (AD) and aging have aging-related cognitive dysfunction with a high incidence. These neurological diseases cause serious cognitive problems in patients' daily life. But the cognitive dysfunction mechanism in-depth of aging is far less known than that of AD. Objective: To reveal the different mechanisms of AD and aging-related cognitive dysfunction, we compared the mechanisms of aging and AD through analysis of differentially expressed genes. Methods: Mice were divided into four groups (3-month C57BL, 16-month C57BL, 3-month 3xTg AD mice, and 16-month 3xTg AD mice) according to genotype and age. The Morris water maze was employed to investigate the spatial cognition of mice. Differential expressions of genes of AD and aging were analyzed through RNA sequencing and GO, KEGG, Reactome analysis, and the dynamic change trend analysis. Microglia was stained with immunofluorescence and its numbers were counted for analysis. Results: The cognitive function of elderly mice were worse through testing with the Morris water maze. The cognitive function of 16-month 3xTg AD mice were worse than 16-month C57BL mice. The alteration tendencies of DE genes were uncovered, and microglia numbers increased during aging and AD progression through immunofluorescence. Conclusion: These results suggest that immune-related pathways might play a critical role in aging and AD-related cognitive dysfunction. Our research will help to provide some new potential targets for treating cognitive dysfunction in aging and AD. [ABSTRACT FROM AUTHOR]

The metabolism disorders are a common convergence of Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). The characteristics of AD are senile plaques and neurofibrillary tangles (NFTs) composed by deposits of amyloid−β (Aβ) and phosphorylated tau, respectively. Advanced glycation end−products (AGEs) are a stable modification of proteins by non−enzymatic reactions, which could result in the protein dysfunction. AGEs are associated with some disease developments, such as diabetes mellitus and AD, but the effects of the glycated γ2 subunit of AMPK on its activity and the roles in AD onset are unknown. Methods: We studied the effect of glycated γ2 subunit of AMPK on its activity in N2a cells. In 3 × Tg mice, we administrated L−arginine once every two days for 45 days and evaluated the glycation level of γ2 subunit and function of AMPK and alternation of pathologies. Results: The glycation level of γ2 subunit was significantly elevated in 3 × Tg mice as compared with control mice, meanwhile, the level of pT172−AMPK was obviously lower in 3 × Tg mice than that in control mice. Moreover, we found that arginine protects the γ2 subunit of AMPK from glycation, preserves AMPK function, and improves pathologies and cognitive deficits in 3 × Tg mice. Conclusions: Arginine treatment decreases glycated γ2 subunit of AMPK and increases p−AMPK levels in 3 × Tg mice, suggesting that reduced glycation of the γ2 subunit could ameliorate AMPK function and become a new target for AD therapy in the future. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of neurodegenerative dementia and one of the top medical concerns worldwide. Currently, the approved drugs to treat AD are effective only in treating the symptoms, but do not cure or prevent AD. Although the exact causes of AD are not understood, it is recognized that tau aggregation in neurons plays a key role. Chuanxiong Rhizoma (CR) has been widely reported as effective for brain diseases such as dementia. Thus, we explored the protections of CR in AD by a tau pathogenesis–based network pharmacology approach. According to ultra-HPLC with triple quadrupole mass spectrometry data and Lipinski's rule of five, 18 bioactive phytochemicals of CR were screened out. They were shown corresponding to 127 tau pathogenesis–related targets, among which VEGFA, IL1B, CTNNB1, JUN, ESR1, STAT3, APP, BCL2L1, PTGS2, and PPARG were identified as the core ones. We further analyzed the specific actions of CR-active phytochemicals on tau pathogenesis from the aspects of tau aggregation and tau-mediated toxicities. It was shown that neocnidilide, ferulic acid, coniferyl ferulate, levistilide A, Z-ligustilide, butylidenephthalide, and caffeic acid can be effective in reversing tau hyperphosphorylation. Neocnidilide, senkyunolide A, butylphthalide, butylidenephthalide, Z-ligustilide, and L-tryptophan may be effective in promoting lysosome-associated degradation of tau, and levistilide A, neocnidilide, ferulic acid, L-tryptophan, senkyunolide A, Z-ligustilide, and butylidenephthalide may antagonize tau-mediated impairments of intracellular transport, axon and synaptic damages, and neuron death (especially apoptosis). The present study suggests that acting on tau aggregation and tau-mediated toxicities is part of the therapeutic mechanism of CR against AD. [ABSTRACT FROM AUTHOR]

Presently, there is a lack of effective disease-modifying drugs for the treatment of Alzheimer's disease (AD). Uncaria rhynchophylla (UR) and its predominant active phytochemicals alkaloids have been studied to treat AD. This study used a novel network pharmacology strategy to identify UR alkaloids against AD from the perspective of AD pathophysiological processes and identified the key alkaloids for specific pathological process. The analysis identified 10 alkaloids from UR based on high-performance liquid chromatography (HPLC) that corresponded to 127 targets correlated with amyloid-β (Aβ) pathology, tau pathology and Alzheimer disease pathway. Based on the number of targets correlated with AD pathophysiological processes, angustoline, angustidine, corynoxine and isocorynoxeine are highly likely to become key phytochemicals in AD treatment. Among the 127 targets, JUN, STAT3, MAPK3, CCND1, MMP2, MAPK8, GSK3B, JAK3, LCK, CCR5, CDK5 and GRIN2B were identified as core targets. Based on the pathological process of AD, angustoline, angustidine and isocorynoxeine were identified as the key UR alkaloids regulating Aβ production and corynoxine, isocorynoxeine, dihydrocorynatheine, isorhynchophylline and hirsutine were identified as key alkaloids that regulate tau phosphorylation. The findings of this study contribute to a more comprehensive understanding of the key alkaloids and mechanisms of UR in the treatment of AD, as well as provide candidate compounds for drug research and development for specific AD pathological processes. [ABSTRACT FROM AUTHOR]

Long‐term or severe lack of protective factors is important in the pathogenesis of neurodegenerative dementia. Progranulin (PGRN), a neurotrophic factor expressed mainly in neurons and microglia, has various neuroprotective effects such as anti‐inflammatory effects, promoting neuron survival and neurite growth, and participating in normal lysosomal function. Mutations in the PGRN gene (GRN) have been found in several neurodegenerative dementias, including frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). Herein, PGRN deficiency and PGRN hydrolytic products (GRNs) in the pathological changes related to dementia, including aggregation of tau and TAR DNA‐binding protein 43 (TDP‐43), amyloid‐β (Aβ) overproduction, neuroinflammation, lysosomal dysfunction, neuronal death, and synaptic deficit have been summarized. Furthermore, as some therapeutic strategies targeting PGRN have been developed in various models, we highlighted PGRN as a potential anti‐neurodegeneration target in dementia. [ABSTRACT FROM AUTHOR]

The studies have shown that 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is involved in Alzheimer's disease (AD) pathology, but the effects of AMPK on AD-like Tau abnormal phosphorylation and its underlying mechanism remains unclear. Herein, we found that the mRNA expression and activity of AMPK are significantly decreased in the brains of the aging C57 mice and 3 × Tg AD mice when compared with their respective control. Moreover, when downregulation of AMPK with AAV-siAMPK-eGFP in the hippocampus CA3 of 3-month-old C57 mice, the mice display AD-like Tau hyperphosphorylation, fear memory impairment, and glycogen synthase kinase-3β (GSK3β) activity increased. On the other hand, there are also AD-like Tau hyperphosphorylation, impairment of fear memory, and AMPK activity decreased in streptozotocin (STZ) mice. Interestingly, AMPK overexpression could efficiently rescue AD-like Tau phosphorylation and brain impairment in STZ mice. Moreover, the activity of GSK3β and the level of Tau phosphorylation (Ser396 and Thr231 sites) were significantly decreased in HEK293 Tau cells transfected by AMPK plasmid or treated with agonists salicylate (SS), but GSK3β agonists Wortmannin (Wort) could ablate AMPK-mediated Tau dephosphorylation. Taken together, the study indicated that AMPK reduces Tau phosphorylation and improves brain function and inhibits GSK3β in AD-like model. These findings proved that AMPK might be a new target for AD in the future. [ABSTRACT FROM AUTHOR]

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD). It is shown that apoE4 preferentially undergoes aberrant cleavage in neurons, yielding neurotoxic C-terminal-truncated apoE4 fragment. Endoplasmic reticulum (ER) stress has also been known to be involved in the pathogenesis of AD. However, little is known about the contribution of ER stress to the neurotoxicity of apoE4 fragment. In the present study, we established the neuron-specific expression human C-terminal-truncated apoE4(1-272) fragment transgenic mice and also transfected apoE4(1-272) fragment in neuroblastoma N2a cells. We found that human apoE4(1-272) fragment could trigger ER stress as evidenced by increasing the expression of ER stress markers both in vivo and in vitro. Meanwhile, the apoE4(1-272) transgenic mice presented obviously AD-like neuropathological changes, including the impairment of spatial learning and memory, prominent axonal morphological changes, and hyperphosphorylation of tau. At the same time, we also found that glycogen synthase kinase-3 activities were significantly increased. Furthermore, these neuropathological changes, especially tau hyperphosphorylation and axonal transport impairment, were significantly rescued by the ER stress protector 4-phenylbutyric acid (4-PBA) in apoE4(1-272)-transfected N2a cells. Pretreatment with 4-PBA not only decreased the protein expression of immunoglobulin binding protein (BiP) and C/EBP-homologous protein (CHOP), but also significantly reversed these defects in axonal transport. These results suggested that the neurotoxic effects of apoE4(1-272) fragment found in AD subjects, at least in part, through triggering ER stress and inducing tau hyperphosphorylation, led to the enduring impairment of axonal transport. [ABSTRACT FROM AUTHOR]

Background Hyperhomocysteinemia is an independent risk factor for dementia, including Alzheimer's disease. Lowering homocysteine levels with folic acid treatment with or without vitamin B12 has shown few clinical benefits on cognition. Methods To verify the effect of emodin, a naturally active compound from Rheum officinale, on hyperhomocysteinemia-induced dementia, rats were treated with homocysteine injection (HCY, 400 μg/kg/d, 2 weeks) via vena caudalis. Afterwards, HCY rats with cognitive deficits were administered intragastric emodin at different concentrations for 2 weeks: 0 (HCY-E0), 20 (HCY-E20), 40 (HCY-E40), and 80 mg/kg/d (HCY-E80). Results β-Amyloid overproduction, tau hyperphosphorylation, and losses of neuron and synaptic proteins were detected in the hippocampi of HCY-E0 rats with cognitive deficits. HCY-E40 and HCY-E80 rats had better behavioral performance. Although it did not reduce the plasma homocysteine level, emodin (especially 80 mg/kg/d) reduced the levels of β-amyloid and tau phosphorylation, decreased the levels of β-site amyloid precursor protein-cleaving enzyme 1, and improved the activity of protein phosphatase 2A. In the hippocampi of HCY-E40 and HCY-E80 rats, the neuron numbers, levels of synaptic proteins, and phosphorylation of the cAMP responsive element-binding protein at Ser133 were increased. In addition, depressed microglial activation and reduced levels of 5-lipoxygenase, interleukin-6, and tumor necrosis factor α were also observed. Lastly, hyperhomocysteinemia-induced microangiopathic alterations, oxidative stress, and elevated DNA methyltransferases 1 and 3β were rescued by emodin. Conclusions Emodin represents a novel potential candidate agent for hyperhomocysteinemia-induced dementia and Alzheimer's disease-like features. [ABSTRACT FROM AUTHOR]

Abstract Objective To explore influence of electroacupuncture (EA) therapy of tonifying the kidney and regulating governor vessel on amyloid beta (Aβ) related degradation enzymes in the hippocampus of a rat model of Alzheimer's disease (AD) induced by Aβ 1-42. Methods Forty Wistar male rats were randomly divided into 4 groups: a normal group, a sham operation group, a model group and an EA group, 10 rats in each one. The rats in normal group were normally fed. The rats in sham operation group were bilaterally injected in the hippocampus with 5 µL of saline and they were normally fed after the injection. The rats in the model group and the EA group were bilaterally injected in the hippocampus with 5 µL of Aβ 1-42 on each side. Rats in the EA group received EA of 5 Hz continuous wave at the "Băihuì (百会 GV20)" and bilateral "Shènshū (肾俞 BL23)" for a duration of 15 min per time every day and continuously for 15 days. After 15 days, the hippocampal expression levels of insulin degrading enzyme (IDE), lipoprotein (LPL), transthyretin (TTR), apolipoprotein E (APoE), α2 macroglobulin (α 2 M) and Aβ 1-42 of the 4 groups were tested by Western blot. Results Compared with the sham operation group, the expression levels of IDE, LPL, TTR, APoE and α2M in the hippocampus were significantly lower (P < 0.05, P < 0.01) and the expression of Aβ 1-42 was significantly higher(P < 0.01) in the model group. Compared with the model group, the expression levels of IDE, LPL, TTR, APoE and α2M in the hippocampus of these rats were significantly lower (P < 0.05, P < 0.01), the expression of Aβ 1-42 was significantly higher(P < 0.01) in the EA group. Conclusion EA therapy of tonifying the kidney and regulating governor vessel can enhance the expression of IDE, LPL, TTR, APoE, and α 2 M in the hippocampus of AD rats injected by Aβ 1-42 , and may consequently promote the degradation of aβ 1-42 to help improve the pathological manifestations of AD and therefore delay its progression. [ABSTRACT FROM AUTHOR]

Abstract: Endoplasmic reticulum (ER) stress is involved in Alzheimer's disease (AD), but the mechanism is not fully understood. Here, we injected tunicamycin (TM), a recognized ER stress inducer, into the brain ventricle of Sprague‐Dawley (SD) rats to induce the unfolded protein response (UPR), demonstrated by the enhanced phosphorylation of pancreatic ER kinase (PERK), inositol‐requiring enzyme‐1 (IRE‐1) and activating transcription factor‐6 (ATF‐6). We observed that UPR induced spatial memory deficits and impairments of synaptic plasticity in the rats. After TM treatment, GSK‐3β was activated and phosphorylation of cAMP response element binding protein at Ser129 (pS129‐CREB) was increased with an increased nuclear co‐localization of pY126‐GSK‐3β and pS129‐CREB. Simultaneous inhibition of GSK‐3β by hippocampal infusion of SB216763 (SB) attenuated TM‐induced UPR and spatial memory impairment with restoration of pS129‐CREB and synaptic plasticity. We concluded that UPR induces AD‐like spatial memory deficits with mechanisms involving GSK‐3β/pS129‐CREB pathway. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by neuritic plaques and neurofibrillary tangles. It is reported that enzymatic degradation of amyloid-β (Aβ) plays a pivotal role in Aβ accumulation and type-2 cannabinoid receptor (CB2R) participates in Aβ processing in the brain; however, the underlying mechanisms remain unclear. We determined that Aβ degradation-related proteins are significantly different between CB2R-/- mice and wild-type (WT) mice via proteomic analysis. Moreover, the data demonstrated that the angiotensin converting enzyme (ACE) and insulin-degrading enzyme (IDE) levels are substantially attenuated, and the Aβ level is significantly enhanced in CB2R-/--Aβ1 - 42 mice compared with that of WT-Aβ1 - 42 mice. Furthermore, Aβ-mediated synaptic dysfunction, the loss of memory associated proteins, and the suppression of glutamatergic transmission are more severe in CB2R-/--Aβ1 - 42 mice than that in WT-Aβ1 - 42 mice. CB2R activation could decrease Aβ1 - 40 and Aβ1 - 42 levels and enhance ACE and IDE levels with its selective agonist JWH133; however, AM630 (CB2R antagonist) abrogates all changes induced by JWH133 in N2a cells with AβPP overexpression. Taken together, our study demonstrated that the deletion of CB2R reduces exogenous Aβ degradation and aggravates the toxicity of Aβ via the reduction of ACE and IDE, which suggests that CB2R is involved in the onset of AD and a potential therapeutic target for AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) underlies dementia for millions of people worldwide with no effective treatment. The dementia of AD is thought stem from the impairments of the synapses because of their critical roles in cognition. Melatonin is a neurohormone mainly released by the pineal gland in a circadian manner and it regulates brain functions in various manners. It is reported that both the melatonin deficit and synaptic impairments are present in the very early stage of AD and strongly contribute to the progress of AD. In the mammalian brains, the effects of melatonin are mainly relayed by two of its receptors, melatonin receptor type 1a (MT1) and 1b (MT2). To have a clear idea on the roles of melatonin in synaptic impairments of AD, this review discussed the actions of melatonin and its receptors in the stabilization of synapses, modulation of long-term potentiation, as well as their contributions in the transmissions of glutamatergic, GABAergic and dopaminergic synapses, which are the three main types of synapses relevant to the synaptic strength. The synaptic protective roles of melatonin in AD treatment were also summarized. Regarding its protective roles against amyloid-β neurotoxicity, tau hyperphosphorylation, oxygenation, inflammation as well as synaptic dysfunctions, melatonin may be an ideal therapeutic agent against AD at early stage. [ABSTRACT FROM AUTHOR]

Hyperphosphorylated tau is the major protein component of neurofibrillary tangles in the brains of patients with Alzheimer’s disease (AD). However, the mechanism underlying tau hyperphosphorylation is not fully understood. Here, we demonstrated that exogenously expressed wild-type human tau40 was detectable in the phosphorylated form at multiple AD-associated sites in cytoplasmic and nuclear fractions from HEK293 cells. Among these sites, tau phosphorylated at Thr205 and Ser214 was almost exclusively found in the nuclear fraction at the conditions used in the present study. With the intracellular tau accumulation, the Ca2+ concentration was significantly increased in both cytoplasmic and nuclear fractions. Further studies using site-specific mutagenesis and pharmacological treatment demonstrated that phosphorylation of tau at Thr205 increased nuclear Ca2+ concentration with a simultaneous increase in the phosphorylation of Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) at Ser196. On the other hand, phosphorylation of tau at Ser214 did not significantly change the nuclear Ca2+/CaMKIV signaling. Finally, expressing calmodulin-binding protein-4 that disrupts formation of the Ca2+/calmodulin complex abolished the okadaic acid-induced tau hyperphosphorylation in the nuclear fraction. We conclude that the intracellular accumulation of phosphorylated tau, as detected in the brains of AD patients, can trigger nuclear Ca2+/CaMKIV signaling, which in turn aggravates tau hyperphosphorylation. Our findings provide new insights for tauopathies: hyperphosphorylation of intracellular tau and an increased Ca2+ concentration may induce a self-perpetuating harmful loop to promote neurodegeneration. [ABSTRACT FROM AUTHOR]

We recently demonstrated that activation of tyrosine receptor kinase B (TrkB) by 7, 8-dihydroxyflavone (7, 8- DHF), the selective TrkB agonist, increased surface alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid ( AMPA) receptors ( AMPARs) AMPA receptor subunit GluR1 (GluA1) subunit expression at the synapses of Fragile X Syndrome mutant mice. This present study investigated the effects of 7, 8- DHF on both memory function and synapse structure in relation to the synapse protein level of AMPARs in the Tg2576 Alzheimer's disease ( AD) mouse model. The study found that chronic oral administration of 7, 8- DHF significantly improved spatial memory and minimized dendrite loss in the hippocampus of Tg2576 mice. A key feature of 7, 8- DHF action was the increased expression of both GluA1 and GluA2 at synapses. Interestingly, 7, 8- DHF had no effect on the attenuation of amyloid precursor protein or Aβ exhibiting in the Tg2576 AD brains, yet it activated the phosphorylation of TrkB receptors and its downstream signals including Ca MKII, Akt, Erk1/2, and cAMP-response element-binding protein. Importantly, cyclotraxin B (a TrkB inhibitor), U0126 (a Ras- ERK pathway inhibitor), Wortmannin (an Akt phosphorylation inhibitor), and KN-93 (a Ca MKII inhibitor) counteracted the enhanced expression and phosphorylation of AMPAR subunits induced by 7, 8- DHF. Collectively, our results demonstrated that 7, 8- DHF acted on TrkB and resolved learning and memory impairments in the absence of reduced amyloid in amyloid precursor protein transgenic mice partially through improved synaptic structure and enhanced synaptic AMPARs. The findings suggest that the application of 7, 8- DHF may be a promising new approach to improve cognitive abilities in AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) has multiple etiopathogenic factors, yet the definitive cause remains unclear and the therapeutic strategies have been elusive. Combination therapy, as one of the promising treatments, has been studied for years and may exert synergistic beneficial effects on AD through polytherapeutic targets. In this study, we tested the effects of a synthesized juxtaposition (named SCR1693) composed of an acetylcholinesterase inhibitor (AChEI) and a calcium channel blocker (CCB) on the hyperhomocysteinemia (HHcy)-induced AD rat model, and found that SCR1693 remarkably improved the HHcy-induced memory deficits and preserved dendrite morphologies as well as spine density by upregulating synapse-associated proteins PSD95 and synapsin-1. In addition, SCR1693 attenuated HHcy-induced tau hyperphosphorylation at multiple AD-associated sites by regulating the activity of protein phosphatase-2A and glycogen synthase kinase-3β. Furthermore, SCR1693 was more effective than individual administration of both donepezil and nilvadipine which were used as AChEI and CCB, respectively, in the clinical practice. In conclusion, our data suggest that the polytherapeutic targeting juxtaposition SCR1693 (AChEI-CCB) is a promising therapeutic candidate for AD. [ABSTRACT FROM AUTHOR]

Hypoxia was shown to be associated with an increased risk of Alzheimer's disease (AD). The effects of hypoxia on the development of AD pathology and spatial memory ability and the possible molecular mechanisms remain poorly understood. In this study, we demonstrate that rats exposed to a hypoxic condition (10% oxygen concentration) for 1, 2, 4 and 8 weeks (6 h each day) displayed spatial memory impairment and increased tau phosphorylation at Ser198/199/202, Thr205, Ser262, Ser396 and Ser404 in the hippocampus. Concomitantly, the levels of Tyr216-phosphorylated glycogen synthase kinase (GSK)-3β (activated form of GSK-3β) and Tyr307-phosphorylated protein phosphatase 2A (inactivated form of PP2A) were significantly increased in the hippocampus of the rats with 1, 2, 4 and 8 weeks of hypoxia exposure, while the levels of methylated PP2A (activated form of PP2A) were significantly decreased in the hippocampus of the rats with 4 and 8 weeks of hypoxia exposure. In addition, the content of malondialdehyde, an indicator of oxidative stress, was elevated, whereas the activity of superoxide dismutase was not significantly changed in the hippocampus of the rats exposed to hypoxia. Taken together, these data demonstrated that hypoxia induced tau hyperphosphorylation and memory impairment in rats, and that the increased tau phosphorylation could be attributed to activation of GSK-3β and inactivation of PP2A. These data suggest that interventions to improve hypoxia may be helpful to prevent the development of AD pathology and cognitive impairment. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Hyperphosphorylated tau is the major component of intracellular neurofibrillary tangles, which is positively correlated with the cognitive decline in Alzheimer's disease (AD). The upstream factors leading to tau hyperphosphorylation are still not fully understood. Endoplasmic reticulum (ER) stress has been indicated in AD pathogenesis and the increased level of binding immunoglobulin protein (Bip), an important ER associated chaperon, is increased in AD brain. Here hyperphosphorylation of tau, activation of glycogen synthase kinase-3β (GSK-3β), and elevation of Bip were induced by ventricular infusion of ER stressors, tunicamycin (TM) and thapsigargin (TG), in rats. GSK-3β was found to be responsible for tau hyperphosphorylation induced by ER stressors both in vivo and in vitro. In addition, inhibited Akt, protein tyrosine phosphatase 1B, and activated Fyn were detected in vivo. Down-regulating Bip by tranfecting its siRNA plasmid significantly revised tau hyperphosphorylation in TG treated HEK293/tau cells, but the activation of GSK-3β was still observed. By immunoprecipitation, we found that the binding levels of Bip to tau and GSK-3β were significantly increased with the elevation of Bip in TM-treated rats. Moreover, in Bip overexpressed HEK293/tau cells, the binding levels of Bip to tau (mainly phosphorylated tau) and GSK-3β were also significantly increased. However, β-catenin, another important substrate of GSK-3β, was not found bound to the increased Bip. All these data suggest an essential role of Bip in GSK-3β dependent tau hyperphosphorylation in ER stress by promoting the binding of GSK-3β to tau. [ABSTRACT FROM AUTHOR]

Hyperhomocysteinemia is associated with an increased risk of Alzheimer's disease (AD). Our previous work has demonstrated that combined folate and vitamin B12 (vit-B12) supplementation prevents tau hyperphosphorylation and memory deficits induced by acute administration of homocysteine in young rats. Here, we further investigated whether folate/vit-B12 supplementation is also effective in aged rats with a chronically high level of homocysteine. 18-month-old rats were injected with homocysteine via the vena caudalis with or without a concurrent folate/vit-B12 supplementation for 28 weeks. We found that hyperhomocysteinemia induced tau hyperphosphorylation and accumulation in hippocampus and cortex. Concurrent signaling changes included the activation of glycogen synthase kinases-3β, cyclin-dependent kinase-5, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and p38MAPK, and inhibition of protein phosphatase 2A. Although the ability to learn was not affected, the aged rats exhibited significant memory deficits. Folate/vit-B12 supplementation attenuated these biochemical and behavioral correlates. These data demonstrate that folate/vit-B12 supplementation is also effective in a chronic hyperhomocysteinemia model in reversing the AD-like tau pathologies and memory deficits. [ABSTRACT FROM AUTHOR]

We have reported recently that inhibition of protein phosphatase (PP)-2A and PP-1 by calyculin A, a specific inhibitor of PP-2A and PP-1, induced Alzheimer-like hyperphosphorylation of tau and spatial memory retention impairment. In this study, we tested the in vivo effects of melatonin on these Alzheimer-like changes. We found that administration of melatonin intraperitoneally for 9 consecutive days before injection of calyculin A could prevent calyculin A-induced synaptophysin loss, memory retention deficits, as well as hyperphosphorylation of tau and neurofilaments. Furthermore, melatonin partially reversed the phosphorylation of the catalytic subunit of PP-2A at Tyrosine 307 (Y307), a crucial site negatively regulating the activity of PP-2A, and reduced the levels of malondialdehyde, a marker of oxidative stress, induced by calyculin A. These results suggest that melatonin could serve as a potential therapeutic agent for preventing Alzheimer-like pathological changes and behavioral abnormality via modulating the activity of PP-2A and oxidative stress. [ABSTRACT FROM PUBLISHER]

ltered neurogenesis has been reported in Alzheimer disease (AD), the most common neurodegenerative disorder characterized with hyperphosphorylated tau and accumulation of β-amyloid (Aβ). Recent studies suggest that tau phosphorylation is essential for hippocampal neurogenesis, however, it is not known whether tau phosphorylation also play a role in neurogenesis of subventricular zone (SVZ), another main progenitor niche in the brain. Here, we examined the expression of phosphorylated tau (p-tau) in SVZ and analyzed the role of p-tau in adult SVZ neurogenesis. We found that the expression of p-tau increased during postnatal development and remains at a high level until adulthood, and the p-tau was colocalized with some SVZ neural precursors. However, up-regulating glycogen synthase kinase-3 (GSK-3), a crucial tau kinase, had no effect on SVZ neurogenesis in adult rat brain. The SVZ neurogenesis was also unaffected in tau knockout and human tau transgenic mice. These results suggest that tau phosphorylation and GSK-3 activation may not be essential for adult SVZ neurogenesis. [ABSTRACT FROM AUTHOR]

Abstract: The microtubule-associated protein tau plays a major role in maintaining the normal morphology of the neurons. The major biological activity of tau is to promote microtubule assembly and stabilize the microtubules. In the brain of Alzheimer''s disease (AD) patients, tau protein is abnormally hyperphosphorylated and thus become incompetent in promoting microtubule assemble and maintaining the stability of the microtubules. These detrimental effects of tau may lead the neurons to degeneration. Recent studies show that tau hyperphorylation may be neuroprotective in the early stages of the disease process. The primary aim of this review is to summarize the latest developments and perspectives in our understanding about the roles of tau hyperphosphorylation in neurodegeneration and neuroprotection. [Copyright &y& Elsevier]

Abstract: Hyperhomocysteinemia increases the risk of Alzheimer''s disease (AD), but the mechanism is elusive. Here, we found that high plasma homocysteine induced by vena caudalis injection for 2 weeks could induce AD-like tau hyperphosphorylation at multiple sites in rat brain hippocampus. Homocysteine inhibited the activity of protein phosphatase 2A (PP2A) with a simultaneously increased Leu309-demethylation and Tyr307-phosphorylation of PP2A catalytic subunit (PP2AC). PP2AC Leu309-demethylation was positively correlated with its Tyr307-phosphorylation; and the abnormally modified PP2AC was incompetent in binding to its regulatory subunit (PP2AB). Homocysteine also activated methylesterase which stimulates demethylation of PP2AC. In hippocampal slices of the homocysteine injected-rats and of the AD patients, the demethylated but not the methylated PP2AC was co-localized with the hyperphosphorylated tau. A simultaneous supplement of folate and vitamin B12 restored partially the plasma homocysteine level and thus significantly antagonized the homocysteine-induced tau hyperphosphorylation and as well as PP2A inactivation and the activity-related modifications of PP2AC. These results suggest that homocysteine may be an upstream effector to induce AD-like tau hyperphosphorylation through inactivating PP2A. [Copyright &y& Elsevier]

Alzheimer's disease (AD) is a growing concern in modern society, and effective drugs for its treatment are lacking. Uncaria rhynchophylla (UR) and its main alkaloids have been studied to treat neurodegenerative diseases such as AD. This study aimed to uncover the key components and mechanism of the anti-AD effect of UR alkaloids through a network pharmacology approach. The analysis identified 10 alkaloids from UR based on HPLC that corresponded to 90 anti-AD targets. A potential alkaloid target-AD target network indicated that corynoxine, corynantheine, isorhynchophylline, dihydrocorynatheine, and isocorynoxeine are likely to become key components for AD treatment. KEGG pathway enrichment analysis revealed the Alzheimers disease (hsa05010) was the pathway most significantly enriched in alkaloids against AD. Further analysis revealed that 28 out of 90 targets were significantly correlated with Aβ and tau pathology. These targets were validated using a Gene Expression Omnibus (GEO) dataset. Molecular docking studies were carried out to verify the binding of corynoxine and corynantheine to core targets related to Aβ and tau pathology. In addition, the cholinergic synapse (hsa04725) and dopaminergic synapse (hsa04728) pathways were significantly enriched. Our findings indicate that UR alkaloids directly exert an AD treatment effect by acting on multiple pathological processes in AD. [ABSTRACT FROM AUTHOR]

[Display omitted] • Dysfunction of neurogenesis in the hippocampal DG were aggravated with month age. • Acupuncture-moxibustion can effectively delay the pathological process of AD. • Acupuncture-moxibustion plays a promising role in the prevention and treatment of AD. Influenced by the global aging population, the incidence of Alzheimer's disease (AD) has increased sharply. In addition to increasing β-amyloid plaque deposition and tau tangle formation, neurogenesis dysfunction has recently been observed in AD. Therefore, promoting regeneration to improve neurogenesis and cognitive dysfunction can play an effective role in AD treatment. Acupuncture and moxibustion have been widely used in the clinical treatment of neurodegenerative diseases because of their outstanding advantages such as early, functional, and benign two-way adjustment. It is urgent to clarify the effectiveness, greenness, and safety of acupuncture and moxibustion in promoting neurogenesis in AD treatment. Senescence-accelerated mouse prone 8 (SAMP8) mice at various ages were used as experimental models to simulate the pathology and behaviors of AD mice. Behavioral experiments, immunohistochemistry, Western blot, and immunofluorescence experiments were used for comparison between different groups. Acupuncture and moxibustion could increase the number of PCNA+ DCX+ cells, Nissl bodies, and mature neurons in the hippocampal Dentate gyrus (DG) of SAMP8 mice, restore the hippocampal neurogenesis, delay the AD-related pathological presentation, and improve the learning and memory abilities of SAMP8 mice. The pathological process underlying AD and cognitive impairment were changed positively by improving the dysfunction of neurogenesis. This indicates the promising role of acupuncture and moxibustion in the prevention and treatment of AD. [ABSTRACT FROM AUTHOR]

Abstract: Tau hyperphosphorylation is a critical event in Alzheimer's disease, in which the neuronal Golgi fragmentation occurs earlier than tau hyperphosphorylation. However, the intrinsic link between Golgi impairment and tau pathology is missing. By electron microscopy and western blotting, we observed in the present study that the neuronal Golgi fragmentation was increased age-dependently with a correlated tau hyperphosphorylation in the brains of C57BL/6 mice aged from 4 to 16 months. Simultaneously, golgin-84 and Golgi reassembly stacking protein 65, 2 important Golgi matrix proteins, were decreased in the brains of elder mice. Further studies in HEK293/tau cells showed that Golgi-disturbing agents, brefeldin A and nocodazole induced tau hyperphosphorylation. Knockdown of golgin-84, not Golgi reassembly stacking protein 65, by small interfering RNA was sufficient to induce tau hyperphosphorylation, while over-expressing golgin-84 arrested the brefeldin A-induced Golgi fragmentation and tau hyperphosphorylation. Finally, we demonstrated that cyclin-dependent kinase-5 and extracellular signal-regulated kinase were activated after golgin-84 knockdown, and simultaneous inhibition of these kinases abolished the golgin-84 deficit-induced tau hyperphosphorylation. These data suggest Golgi fragmentation could be an upstream event triggering tau hyperphosphorylation through golgin-84 deficit-induced activation of cyclin-dependent kinase-5 and extracellular signal-regulated kinase. [Copyright &y& Elsevier]