Tau exacerbates excitotoxic brain damage in an animal model of stroke

Bi, Mian; Gladbach, Amadeus; Eersel, Janet van; Ittner, Arne; Przybyla, Magdalena; Hummel, Annika van; Chua, Sook Wern; Hoven, Julia van der; Lee, Wei S.; Müller, Julius; Parmar, Jasneet; Jonquières, Georg von; Stefen, Holly; Guccione, Ernesto; Fath, Thomas; Housley, Gary D.; Klugmann, Matthias; Ke, Yazi D.; Ittner, Lars M.

doi:10.1038/s41467-017-00618-0

Cited by 134 publications

(112 citation statements)

References 89 publications

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“…Indeed, a handful of studies have reported that brain ischemia is a non‐neglectable factor driving the development of AD through dysregulated expression of AD‐associated genes, such as Aβ precursor processing genes and tau protein gene . Lastly, tau protein, a core hallmark of AD, can exacerbate brain injury in experimental IS through tau‐mediated iron export and excitotoxicity . Taken together, we hypothesized that there might be a shared genetic basis underlying these connections between AD and IS.…”

Section: Introductionmentioning

confidence: 94%

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Shared genes between Alzheimer’s disease and ischemic stroke

Wei

Cui

et al. 2019

CNS Neurosci Ther

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Summary Aims Although converging evidence from experimental and epidemiological studies indicates Alzheimer's disease (AD) and ischemic stroke (IS) are related, the genetic basis underlying their links is less well characterized. Traditional SNP‐based genome‐wide association studies (GWAS) have failed to uncover shared susceptibility variants of AD and IS. Therefore, this study was designed to investigate whether pleiotropic genes existed between AD and IS to account for their phenotypic association, although this was not reported in previous studies. Methods Taking advantage of large‐scale GWAS summary statistics of AD (17,008 AD cases and 37,154 controls) and IS (10,307 IS cases and 19,326 controls), we performed gene‐based analysis implemented in VEGAS2 and Fisher's meta‐analysis of the set of overlapped genes of nominal significance in both diseases. Subsequently, gene expression analysis in AD‐ or IS‐associated expression datasets was conducted to explore the transcriptional alterations of pleiotropic genes identified. Results 16 AD‐IS pleiotropic genes surpassed the cutoff for Bonferroni‐corrected significance. Notably, MS4A4A and TREM2 , two established AD‐susceptibility genes showed remarkable alterations in the spleens and brains afflicted by IS, respectively. Among the prioritized genes identified by virtue of literature‐based knowledge, most are immune‐relevant genes ( EPHA1 , MS4A4A , UBE2L3 and TREM2 ), implicating crucial roles of the immune system in the pathogenesis of AD and IS. Conclusions The observation that AD and IS had shared disease‐associated genes offered mechanistic insights into their common pathogenesis, predominantly involving the immune system. More importantly, our findings have important implications for future research directions, which are encouraged to verify the involvement of these candidates in AD and IS and interpret the exact molecular mechanisms of action.

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Section: Introductionmentioning

confidence: 94%

“…9,10 Lastly, tau protein, a core hallmark of AD, can exacerbate brain injury in experimental IS through tau-mediated iron export and excitotoxicity. 11,12 Taken together, we hypothesized that there might be a shared genetic basis underlying these connections between AD and IS.…”

Section: Introductionmentioning

confidence: 99%

Shared genes between Alzheimer’s disease and ischemic stroke

Wei

Cui

et al. 2019

CNS Neurosci Ther

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“…Hydrogen peroxide treatment caused a morphological degeneration of OLGs with loss of cellular processes; this morphological degeneration is preceded by a profound dephosphorylation of tau protein [48]. A similar H 2 O 2 -induced dephosphorylation of tau protein in OLGs was previously observed in neurons during continuous exposure to H 2 O 2 [50]; the dephosphorylation of tau protein may be an integral part of the cellular response to oxidative stress, and it has been reported following human stroke, head injury, and brain heat shock [51,52,53]. …”

Section: Mechanisms Of Tau Regulationmentioning

confidence: 68%

Tau in Oligodendrocytes Takes Neurons in Sickness and in Health

LoPresti

2018

IJMS

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Oligodendrocytes (OLGs), the myelin-forming cells of the central nervous system (CNS), are lifelong partners of neurons. They adjust to the functional demands of neurons over the course of a lifetime to meet the functional needs of a healthy CNS. When this functional interplay breaks down, CNS degeneration follows. OLG processes are essential features for OLGs being able to connect with the neurons. As many as fifty cellular processes from a single OLG reach and wrap an equal number of axonal segments. The cellular processes extend to meet and wrap axonal segments with myelin. Further, transport regulation, which is critical for myelination, takes place within the cellular processes. Because the microtubule-associated protein tau plays a crucial role in cellular process extension and myelination, alterations of tau in OLGs have deleterious effects, resulting in neuronal malfunction and CNS degeneration. Here, we review current concepts on the lifelong role of OLGs and myelin for brain health and plasticity. We present key studies of tau in OLGs and select important studies of tau in neurons. The extensive work on tau in neurons has considerably advanced our understanding of how tau promotes either health or disease. Because OLGs are crucial to neuronal health at any age, an understanding of the functions and regulation of tau in OLGs could uncover new therapeutics for selective CNS neurodegenerative diseases.

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“…7). During ischemia/reperfusion, excessive glutamate accumulates in the synaptic cleft and extracellular space of neuronal cells, leading to neuronal cell death [33]. The GluN2D subunit has the highest affinity for glutamate (EC 50 : 0.4 µM) compared to the other GluN2 subunits (EC 50 : 1 ~ 4 µM) [34].…”

Section: Discussionmentioning

confidence: 99%

Pituitary Adenylate Cyclase Activating Polypeptide Elicits Neuroprotection Against Acute Ischemic Neuronal Cell Death Associated with NMDA Receptors

Kaneko

Tuazon

et al. 2018

Cell Physiol Biochem

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Background/Aims: The endogenous neurotrophic peptides pituitary adenylate cyclase-activating polypeptides (PACAP-27/38) protect against stroke, but the molecular mechanism remains unknown. Methods: Primary rat neural cells were exposed to PACAP-27 or PACAP-38 before induction of experimental acute ischemic stroke via oxygen-glucose deprivation-reperfusion (OGD/R) injury. To reveal PACAP’s role in neuroprotection, we employed fluorescent live/dead cell viability and caspase 3 assays, optical densitometry of mitochondrial dehydrogenase and cell growth, glutathione disulfide luciferase activity, ELISA for high mobility group box1 extracellular concentration, ATP bioluminescence, Western blot analysis of PACAP, NMDA subunits, apoptosis regulator Bcl-2, social interaction hormone oxytocin, and trophic factor BDNF, and immunocytochemical analysis of PACAP. Results: Both PACAP-27 and PACAP-38 (PACAP-27/38) increased cell viability, decreased oxidative stress-induced cell damage, maintained mitochondrial activity, prevented the release of high mobility group box1, and reduced cytochrome c/caspase 3-induced apoptosis. PACAP-27/38 increased the protein expression levels of BDNF, Bcl-2, oxytocin, and precursor PACAP. N-methyl-D-aspartate receptor (NMDAR)-induced excitotoxicity contributes to the cell death associated with stroke. PACAP-27/38 modulated the protein expression levels of NMDAR subunits. PACAP-27/38 increased the protein expression levels of the GluN1 subunit, and decreased that of the GluN2B and GluN2D subunits. PACAP-27, but not PACAP-38, increased the expression level of the GluN2C subunit. Conclusion: This study provides evidence that PACAP regulated NMDAR subunits, affording neuroprotection after OGD/R injury.

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Tau exacerbates excitotoxic brain damage in an animal model of stroke

Cited by 134 publications

References 89 publications

Shared genes between Alzheimer’s disease and ischemic stroke

Shared genes between Alzheimer’s disease and ischemic stroke

Tau in Oligodendrocytes Takes Neurons in Sickness and in Health

Pituitary Adenylate Cyclase Activating Polypeptide Elicits Neuroprotection Against Acute Ischemic Neuronal Cell Death Associated with NMDA Receptors

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