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PubMed: 17403556

Title
Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers.
Journal
Neurobiology of aging
Volume
29
Issue
None
Pages
1334-47
Date
2008-09-01
Authors
De Felice FG | Klein WL | Acton PJ | Bigio EH | Chen-Dodson E | Fernandez SJ | Jerecic J | Kinney GG | Lacor PN | Lambert MP | Shughrue PJ | Velasco PT | Wu D

Evidence 96076d0d14
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Interestingly, we found that tau hyperphosphorylation at Thr231 was completely blocked by the Src family tyrosine kinase inhibitor, 4-amino-5-(4- chlorophenyl)-7(t-butyl)pyrazol(3,4-d)pyramide (PP1), and by the phosphatidylinositol 3-kinase inhibitor, LY294002 (Fig. 5).

a(CHEBI:LY294002) decreases p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

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a(MESH:"4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine") decreases p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

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Inhibition occurred even though ADDLs were still bound to cell surfaces, indicating that those kinases are involved in signal transduction coupling between ADDL binding and tau hyperphosphorylation.

a(CHEBI:LY294002) decreases bp(GO:"signal transduction") View Subject | View Object

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a(MESH:"4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine") decreases bp(GO:"signal transduction") View Subject | View Object

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bp(GO:"signal transduction") increases complex(a(HBP:"amyloid-beta derived diffusible ligands"), p(HGNC:MAPT)) View Subject | View Object

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complex(a(HBP:"amyloid-beta derived diffusible ligands"), p(HGNC:MAPT)) increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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Evidence acbfe086e8
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Moreover, the presence of large extracellular aggregates in NU1-treated cultures (Fig. 5N) suggests that the antibody effectively sequesters ADDLs and prevents their interactions with neurons (Fig. 5O). No inhibition of ADDL binding was associated with PP1 and LY294002 (Fig. 5H, I, K and L, respectively), but both kinase inhibitors effectively blocked ADDL-induced tau hyperphosphorylation (Fig. 5G and J).

a(CHEBI:LY294002) decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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a(HBP:"amyloid-beta antibody, NU1") decreases complex(a(HBP:"amyloid-beta derived diffusible ligands"), a(MESH:Neurons)) View Subject | View Object

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a(MESH:"4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine") decreases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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Evidence 3887705b41
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NU1 completely blocked the increase in P-Ser404 and P-Thr231 phosphotau levels induced by ADDLs (Fig. 3D–H).

a(HBP:"amyloid-beta antibody, NU1") decreases act(a(HBP:"amyloid-beta derived diffusible ligands")) View Subject | View Object

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Evidence 4d08d5bce6
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Importantly, pre-incubation of AD brain extracts with NU1 significantly blocked the increase in Thr231 phosphotau immunofluorescence (Fig. 6G), establishing the tau hyperphosphorylation was induced by Abeta oligomers in the AD brain extracts. NU1 also prevented the binding of brain-derived ADDLs to synaptic hot-spots (Fig. 6H and I). In NU1-treated cultures, the presence of large extracellular aggregates indicates that the antibody sequesters ADDLs and prevents their interactions with neurons (Fig. 6I).

a(HBP:"amyloid-beta antibody, NU1") decreases complex(a(HBP:"amyloid-beta derived diffusible ligands"), a(MESH:Neurons)) View Subject | View Object

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MeSH
Alzheimer Disease
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a(HBP:"amyloid-beta antibody, NU1") decreases p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

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Alzheimer Disease
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a(HBP:"amyloid-beta antibody, NU1") decreases complex(a(GO:synapse), a(HBP:"amyloid-beta derived diffusible ligands")) View Subject | View Object

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Alzheimer Disease
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a(HBP:"amyloid-beta oligomers") increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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Alzheimer Disease
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Evidence 0b57d99cf1
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At longer incubation times (48 and 96 h) ADDLs caused a progressive decrease in MTT reduction (Fig. 1B), which can be due to altered trafficking (Liu et al., 1998) as well as cell death.

a(HBP:"amyloid-beta derived diffusible ligands") decreases bp(MESH:"Cell Survival") View Subject | View Object

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While vehicle treated cells (Fig. 2A and B) exhibited low phosphotau immunofluorescence, cells treated with 1 microM biotinylated ADDLs (bADDLs) for 6 h (Fig. 2C and D) showed a significant increase in P-tau immunofluorescence (Fig. 2D).

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We then investigated whether bADDLs also induced tau phosphorylation in rat hippocampal neurons. To this end, we initially used frozen dissociated rat hippocampal cell preparations (Cambrex). Cells were maintained in the presence of 1M bADDLs (Fig. 2I and J) or vehicle (not shown) for 6 h at 37 ◦C. We observed a marked P-tau immunostaining in a subpopulation of neurons that also had ADDLs bound (Fig. 2I, arrowheads), while cells that did not bind bADDLs had no AT8 staining (Fig. 2J).

a(HBP:"amyloid-beta derived diffusible ligands") increases p(RGD:Mapt, pmod(Ph)) View Subject | View Object

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Hippocampus
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Evidence a2a4de65d4
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Following exposure to ADDLs, double-label immunofluorescence microscopy showed high levels of tau phosphorylated at Thr231, which discriminates among AD and non-AD subjects and patients with other forms of dementia (Hampel et al., 2004, 2003), in neurons with prominent dendritic ADDL binding (detected with NU1, Fig. 2K–M). ADDL binding to synaptic hot-spots in hippocampal neurons is evident in images at highermagnification (60×objective, PanelsLand M).

a(HBP:"amyloid-beta derived diffusible ligands") increases p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

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a(HBP:"amyloid-beta derived diffusible ligands") increases complex(a(GO:synapse), a(HBP:"amyloid-beta derived diffusible ligands")) View Subject | View Object

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Hippocampus
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p(HGNC:MAPT, pmod(Ph, Thr, 231)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

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Evidence 8deaf91293
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Vehicle-treated neurons (Fig. 3A and E) exhibited very low phosphotau immunofluorescence, but neurons treated for 4 h with 500nM ADDLs showed significantly higher levels in immunofluorescence of P-Ser404 and P-Thr231 tau (Fig. 3B and F, respectively). Neurons treated for 4 h with 10M Abeta fibrils also showed an increase in immunofluorescence of P-Ser404 and P-Thr231 tau (Fig. 3C and G, respectively).

a(HBP:"amyloid-beta derived diffusible ligands") increases p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

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a(HBP:"amyloid-beta derived diffusible ligands") increases p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

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a(HBP:"amyloid-beta fibrils") increases p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

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a(HBP:"amyloid-beta fibrils") increases p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

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Evidence ff8da3901c
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Verification of the findings from immunofluorescence microscopy was provided by Western blot analysis of hippocampal neuronal lysates with P404, P231 and P181 antiphosphotau antibodies. A 4 h exposure to 500nM ADDLs resulted in a significant increase in tau phosphorylated at the three epitopes, to levels similar to those observed after exposure to 10 M Abeta fibrils (Fig. 4A–D).

a(HBP:"amyloid-beta derived diffusible ligands") increases p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

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a(HBP:"amyloid-beta derived diffusible ligands") increases p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

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a(HBP:"amyloid-beta derived diffusible ligands") increases p(HGNC:MAPT, pmod(Ph, Thr, 181)) View Subject | View Object

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a(HBP:"amyloid-beta fibrils") increases p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

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a(HBP:"amyloid-beta fibrils") increases p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

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a(HBP:"amyloid-beta fibrils") increases p(HGNC:MAPT, pmod(Ph, Thr, 181)) View Subject | View Object

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Evidence 53c57af8dd
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Hippocampal neurons exposed to Abeta fibrils rather than oligomers also showed elevated P-tau immunofluorescence (Fig. 2N–P) However, although fibrils could be seen attached to neurons, they did not bind in the synaptic pattern observed for ADDLs (Fig. 2O and P).

a(HBP:"amyloid-beta fibrils") increases p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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These results confirm that the tau hyperphosphorylation stimulated by soluble ADDL preparations is indeed oligomer-induced. Tau hyperphosphorylation induced by 10M Abeta fibrils (Fig. 3N) was partially blocked (Fig. 3O), consistent with shared epitopes between oligomers and fibrils.

a(HBP:"amyloid-beta oligomers") increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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Evidence eac936e5c1
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AD brains could induce AD-type tau hyperphosphorylation. Consistent with the results obtained with synthetic ADDLs, we found that treatment of mature hippocampal neuronal cultures with a soluble AD brain extract led to a significant increase in P231 tau phosphorylation (Fig. 6D) compared to cultures treated with a non-AD brain extract (Fig. 6A).

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") increases p(HGNC:MAPT, pmod(Ph, Thr, 231)) View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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Evidence a5618765cf
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We note that these observed increases in tau phosphorylation occurred well before neuronal death (Fig. 1B), consistent with this pathology representing an early stage in neurodegeneration.

p(HGNC:MAPT, pmod(Ph)) positiveCorrelation path(HBP:Neurodegeneration) View Subject | View Object

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path(HBP:Neurodegeneration) positiveCorrelation p(HGNC:MAPT, pmod(Ph)) View Subject | View Object

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