GSK-3 and Tau: A Key Duet in Alzheimer's Disease.
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ABSTRACT:
SUBMITTER: Sayas CL
PROVIDER: S-EPMC8063930 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abnormal hyperphosphorylation of tau is pivotally involved in the pathogenesis of Alzheimer's disease (AD) and related tauopathies. Glycogen synthase kinase 3? (GSK-3?) is a primary tau kinase that is most implicated in tau pathology in AD. However, the exact molecular nature of GSK-3? involved in AD is unclear. In the present study, we found that GSK-3? was truncated at C-terminus and correlated with over-activation of calpain I in AD brain. Truncation of GSK-3? was positively correlated with tau hyperphosphorylation, tangles score and Braak stage in human brain. Calpain I proteolyzed GSK-3? in vitro at C-terminus, leading to an increase of its kinase activity, but keeping its characteristic to preferentially phosphorylate the protein kinase A-primed tau. Excitotoxicity induced by kainic acid (KA) caused GSK-3? truncation at C-terminus and hyperphosphorylation of tau in mouse brain. Inhibition of calpain prevented the KA-induced changes. These findings suggest that truncation of GSK-3? by Ca(2+)/calpain I markedly increases its activity and involvement of this mechanism probably is responsible for up-regulation of GSK-3? and consequent abnormal hyperphosphorylation of tau and neurofibrillary degeneration in AD.
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Project description:Dysregulated microRNA (miRNA) expression in the brain can contribute to cognitive dysfunction and aberrant tau hyperphosphorylation in Alzheimer's disease (AD). Several studies have reported a role for microRNA-23b-3p (miR-23b-3p) in various neurologic disorders; however, its involvement in cognition-related functions remains unclear. In the present study, we investigated the potential therapeutic effects and mechanisms of miR-23b-3p in AD. miRNA profiles in the cortex of amyloid precursor protein (APP)/presenilin 1 (PS1) double transgenic mice (APP/PS1 mice) demonstrated that miR-23b-3p was reduced. This decrease was verified in APPswe cells, SAMP8 mouse brains, and plasma from AD patients. Furthermore, glycogen synthase kinase-3β (GSK-3β), a major tau kinase implicated in tau pathology, was identified as a target of miR-23b-3p. Functional in vivo studies demonstrated that intracerebroventricular delivery of miR-23b-3p in APP/PS1 mice ameliorated cognitive deficits, histopathological changes, and tau phosphorylation immunoreactivity at several sites by inhibiting GSK-3β expression and activation. Similarly, the upregulation of miR-23b-3p in APPswe cells inhibited GSK-3β-mediated tau hyperphosphorylation, Aβ1-42 generation, and neuronal apoptosis, resulting in the suppression of the GSK-3β/p-tau and Bax/caspase-3 pathways. Collectively, our findings strongly support the hypothesis that miR-23b-3p plays a neuroprotective role in AD, thereby identifying miR-23b-3p as a promising therapeutic target for AD.
| S-EPMC9092887 | biostudies-literature
Project description:INTRODUCTION:Alzheimer's dementia (AD) is the most common form of dementia in the World. Pathologically, it is characterized by extracellular ?-amyloid plaques and intraneuronal neurofibrillary tangles (NFTs). The latter is composed of irregular, pathological forms of the tau protein. Currently, FDA-approved symptomatic treatments are limited to the targeting of cholinergic deficits and glutamatergic dysfunctions. However, as understanding of ?-amyloid plaques and NFTs expands, these dysfunctional proteins represent potential therapeutic interventions. The present review article evaluates active and passive immunotherapies in clinical development for AD to date and their potential to significantly improve the treatment of AD going forward. AREAS COVERED:All clinical trials that have targeted ?-amyloid to date have produced somewhat disappointing results, leading to a shift in intervention focus to targeting tau protein. A key component in understanding the value of targeting tau in therapeutic paradigms has come from the conceptualization of prion-like pathological spread of tau isoforms from neuron to neuron, and referred to as 'tauons'. Immunotherapies currently under investigation include approaches aiming at preventing pathological tau aggregation, stabilizing microtubules, and blocking of tauons. EXPERT OPINION:A multi-targeted approach that would use biologics targeting tau offers great promise to the development of effective AD therapeutic interventions.
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Project description:Identification of posttranlational modifications of Tau in Alzheimer's disease
2022-05-19 | PXD031417 | Pride
Project description:Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a "prion-like" spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate-i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau-, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease.
| S-EPMC5928393 | biostudies-literature
Project description:Aging and neurodegenerative disease are characterized by genomic instability in neurons, including aberrant activation and mobilization of transposable elements (TEs). Integrating studies of human postmortem brain tissue and Drosophila melanogaster models, we investigate TE activation in association with Tau pathology in Alzheimer's disease (AD). Leveraging RNA sequencing from 636 human brains, we discover differential expression for several retrotransposons in association with neurofibrillary tangle burden and highlight evidence for global TE transcriptional activation among the long interspersed nuclear element 1 and endogenous retrovirus clades. In addition, we detect Tau-associated, active chromatin signatures at multiple HERV-Fc1 genomic loci. To determine whether Tau is sufficient to induce TE activation, we profile retrotransposons in Drosophila expressing human wild-type or mutant Tau throughout the brain. We discover heterogeneous response profiles, including both age- and genotype-dependent activation of TE expression by Tau. Our results implicate TE activation and associated genomic instability in Tau-mediated AD mechanisms.
| S-EPMC6181645 | biostudies-literature
Project description:Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder. A defining hallmark of the AD brain is the presence of intraneuronal neurofibrillary tangles (NFTs) which are made up of abnormally modified tau, with aberrant phosphorylation being the most studied posttranslational modification (PTM). Although the accumulation of tau as NFTs is an invariant feature of the AD brain, it has become evident that these insoluble aggregates are likely not the primary pathogenic form of tau, rather soluble forms of tau with abnormal PTMs are the mediators of toxicity. The most prevalent PTM on tau is phosphorylation, with the abnormal modification of specific residues on tau playing a key role in its toxicity. Even though it is widely accepted that tau with aberrant PTMs facilitates neurodegeneration, the precise cellular mechanisms remain unknown. Nonetheless, there is an evolving conceptual framework that an important contributing factor may be selective pathological tau species compromising mitochondrial biology. Understanding the mechanisms by which tau with site-specific PTM impacts mitochondria is crucial for understanding the role tau plays in AD. Here, we provide a brief introduction to tau and its phosphorylation and function in a physiological context, followed by a discussion of the impact of soluble phosphorylated tau species on neuronal processes in general and mitochondria more specifically. We also discuss how therapeutic strategies that attenuate pathological tau species in combination with treatments that improve mitochondrial biology could be a potential therapeutic avenue to mitigate disease progression in AD and other tauopathies.
| S-EPMC7544674 | biostudies-literature
Project description:Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by abnormal extracellular aggregates of amyloid-b and intraneuronal hyperphosphorylated, tau tangles and neuropil threads. Microglia, the tissue-resident macrophages of the central nervous system (CNS), are important for CNS homeostasis and implicated in AD pathology. In amyloid mouse models, a phagocytic/activated microglia phenotype has been identified. How increasing levels of amyloid-b and tau pathology affect human microglia transcriptional profiles is unknown. Here, we performed snRNAseq on 482,472 nuclei from non-demented control brains and AD brains containing only amyloid-b plaques or both amyloid-b plaques and tau pathology. Within the microglia population, distinct expression profiles were identified of which two were AD pathology-associated. The phagocytic/activated AD1-microglia population abundance strongly correlated with tissue amyloid-b load and localized to amyloid-b plaques. The AD2-microglia abundance strongly correlated with tissue phospho-tau load and these microglia were more abundant in samples with over tau pathology. This full characterization of human disease associated microglia phenotypes provides new insights in the pathophysiological role of microglia in AD and offers new targets for microglia-state-specific therapeutic strategies.
2021-02-20 | GSE148822 | GEO
Project description:Alzheimer's disease (AD) is the most common form of dementia characterized by progressive loss of cognitive functions due to neuronal death mainly in the hippocampal and cortical brain. Sulforaphene (SF) is one of the main isothiocyanates isolated from a Chinese herb Raphani Semen. In this study, we aimed to investigate the neuroprotective effects of SF using in vitro and in vivo models of AD. Streptozotocin (STZ) was intracranially injected into the rats; then, SF (25 and 50 mg/kg) was given orally once a day for 6 consecutive weeks. After drug treatment, the cognitive functions were assessed using the Morris Water Maze Test (MWMT). After the MWMT, the rats were euthanized and brain tissues were collected. In the in vitro test, BV-2 microglia were pretreated with SF (1 and 2 μM) for 1 h and then stimulated with lipopolysaccharide (LPS) for another 23 h. Both molecular and histological methods were used to unravel the action mechanisms and elucidate the signaling pathway. The MWMT results showed that SF treatment significantly improved the STZ-induced cognitive deficits in rats. SF treatment markedly suppressed the production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) but increased the release of IL-10 in the STZ-treated rats. In addition, SF significantly inhibited the phosphorylation of tau protein at Thr205, Ser396, and Ser404 sites, while enhancing the ratios of p-Akt (Ser473)/Akt and p-GSK-3β (Ser9)/GSK-3β in the hippocampus of the STZ-treated rats. On the other hand, SF (1 and 2 μM) treatment also markedly attenuated the cytotoxicity induced by LPS in BV-2 cells. In addition, SF treatment obviously suppressed the releases of nitric oxide (NO), TNF-α, and IL-6 in the LPS-stimulated BV-2 cells. Moreover, SF treatment significantly mitigated the nuclear translocation of p-NF-κB p65 and the ratio of p-GSK-3β (Ser9)/GSK-3β in LPS-stimulated BV-2 cells. Taken together, SF possessed neuroprotective effects against the STZ-induced cognitive deficits in rats and LPS-induced neuroinflammation in BV-2 cells via modulation of the PI3K/Akt/GSK-3β pathway and inhibition of the NF-κB activation, suggesting that SF is a promising neuroprotective agent worthy of further development into AD treatment.
| S-EPMC7502131 | biostudies-literature
Project description:Alzheimer's disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid ? peptide (A?), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5' and 3' regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner.
| S-EPMC3626266 | biostudies-literature