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PubMed: 22156579

Title
A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines.
Journal
Human molecular genetics
Volume
21
Issue
None
Pages
1384-90
Date
2012-03-15
Authors
Lu B | Malenka R | Polepalli J | Rajadas J | Wagh D | Yu W

Evidence ddf3fd103f
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Consistent with previous reports (11,34), treatment of rat hippocampal neurons with synthetic Aβ, prepared using a well-characterized procedure that enriches for Aβ oligomers (37), resulted in increased tau phosphorylation at the 12E8 sites (Fig. 2A), suggesting that Aβ treatment had activated MARK kinases. Increased phosphorylation of tau at a site recognized by the PHF-1 phospho-tau antibody was also observed (data not shown).

a(CHEBI:"amyloid-beta") increases p(HGNC:MARK4) View Subject | View Object

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hippocampal formation

a(CHEBI:"amyloid-beta") positiveCorrelation a(HBP:"Tau epitope, PHF1") View Subject | View Object

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hippocampal formation

a(HBP:"Tau epitope, PHF1") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

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hippocampal formation

Evidence ec5382d64e
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Overexpression of MARK4 led to tau hyperphosphorylation, reduced expression of synaptic markers, and loss of dendritic spines and synapses, phenotypes also observed after Aβ treatment. Importantly, expression of a non-phosphorylatable form of tau with the PAR-1/MARK site mutated blocked the synaptic toxicity induced by MARK4 overexpression or Aβ treatment. To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels.

a(GO:"dendritic spine") negativeCorrelation p(HGNC:MARK4) View Subject | View Object

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hippocampal formation

a(GO:synapse) negativeCorrelation p(HGNC:MARK4) View Subject | View Object

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hippocampal formation

p(HGNC:MARK4) increases a(HBP:"Tau epitope, 12E8") View Subject | View Object

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hippocampal formation

p(HGNC:MARK4) negativeCorrelation act(p(RGD:Dlg4)) View Subject | View Object

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hippocampal formation

p(HGNC:MARK4) negativeCorrelation p(RGD:Gria1) View Subject | View Object

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hippocampal formation

p(HGNC:MARK4) negativeCorrelation a(GO:"dendritic spine") View Subject | View Object

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hippocampal formation

p(HGNC:MARK4) negativeCorrelation a(GO:synapse) View Subject | View Object

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hippocampal formation

act(p(RGD:Dlg4)) negativeCorrelation p(HGNC:MARK4) View Subject | View Object

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hippocampal formation

p(RGD:Gria1) negativeCorrelation p(HGNC:MARK4) View Subject | View Object

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Uberon
hippocampal formation

Evidence ea6e3b7599
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We first confirmed that expression of an MKI-GFP fusion protein in rat hippocampal neurons effectively attenuated MARK4-mediated phosphorylation of both endogenous tau (Fig. 3A) and transfected human tau at the 12E8 sites (Fig. 3B). Phosphorylation of tau at the PHF-1 site was also reduced by MKI (Fig. 3A). It is possible that the PHF-1 site is also targeted by PAR-1/MARKs in vivo, or that the phosphorylation of tau at the 12E8 sites is a prerequisite for PHF-1 site phosphorylation, as the 12E8 sites were previously shown to be required for tau phosphorylation at other sites

a(HBP:"Tau epitope, 12E8") positiveCorrelation a(HBP:"Tau epitope, PHF1") View Subject | View Object

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a(HBP:"Tau epitope, PHF1") positiveCorrelation a(HBP:"Tau epitope, 12E8") View Subject | View Object

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a(HBP:"Tau epitope, PHF1") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 396)) View Subject | View Object

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a(HBP:"Tau epitope, PHF1") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

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p(HGNC:MAPT, pmod(Ph, Ser, 396)) positiveCorrelation a(HBP:"Tau epitope, PHF1") View Subject | View Object

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p(HGNC:MAPT, pmod(Ph, Ser, 404)) positiveCorrelation a(HBP:"Tau epitope, PHF1") View Subject | View Object

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p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation act(p(INTERPRO:"Kinase associated domain 1 (KA1)"), ma(kin)) View Subject | View Object

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p(HGNC:MAPT, pmod(Ph, Ser, 356)) positiveCorrelation act(p(INTERPRO:"Kinase associated domain 1 (KA1)"), ma(kin)) View Subject | View Object

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act(p(INTERPRO:"Kinase associated domain 1 (KA1)"), ma(kin)) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

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act(p(INTERPRO:"Kinase associated domain 1 (KA1)"), ma(kin)) positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 356)) View Subject | View Object

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Evidence 285c8a477f
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To probe the involvement of endogenous MARK kinases in mediating the synaptic toxicity of Aβ, we employed a peptide inhibitor capable of effectively and specifically inhibiting the activities of all PAR-1/MARK family members. This inhibitor abrogated the toxic effects of Aβ oligomers on dendritic spines and synapses as assayed at the morphological and electrophysiological levels.

act(a(HBP:"amyloid-beta oligomers")) positiveCorrelation p(INTERPRO:"Kinase associated domain 1 (KA1)") View Subject | View Object

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p(INTERPRO:"Kinase associated domain 1 (KA1)") positiveCorrelation act(a(HBP:"amyloid-beta oligomers")) View Subject | View Object

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