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PubMed: 22299660

Title
PP2A and Alzheimer disease.
Journal
Current Alzheimer research
Volume
9
Issue
None
Pages
248-56
Date
2012-02-01
Authors
Ferrer I | Torrent L

Evidence d71646d91e
JSON

Similar findings have been observed in metabolically active rat brain slices, where a selective inhibition of PP2A with OA results in an aberrant phosphorylation of tau at the same residues seen in AD brains at serines (Ser) 198, 199, 202, 396, 404, 422 and 262 [11, 47, 48].

a(CHEBI:"okadaic acid") decreases act(p(FPLX:PPP2)) View Subject | View Object

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a(CHEBI:"okadaic acid") increases p(HGNC:MAPT, pmod(Ph, Ser, 189)) View Subject | View Object

Appears in Networks:

a(CHEBI:"okadaic acid") increases p(HGNC:MAPT, pmod(Ph, Ser, 199)) View Subject | View Object

Appears in Networks:

a(CHEBI:"okadaic acid") increases p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

Appears in Networks:

a(CHEBI:"okadaic acid") increases p(HGNC:MAPT, pmod(Ph, Ser, 396)) View Subject | View Object

Appears in Networks:

a(CHEBI:"okadaic acid") increases p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

Appears in Networks:

a(CHEBI:"okadaic acid") increases p(HGNC:MAPT, pmod(Ph, Ser, 422)) View Subject | View Object

Appears in Networks:

a(CHEBI:"okadaic acid") increases p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 189)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 199)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 202)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 262)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 396)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 404)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(HGNC:MAPT, pmod(Ph, Ser, 422)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 189)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 199)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 202)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 396)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 404)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 422)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:MAPT, pmod(Ph, Ser, 262)) View Subject | View Object

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Evidence cb23f6bb10
JSON

Further experiments based on the injection of a PP2A inhibitor in the rat hippocampus demon- strated tau hyper-phosphorylation, and learning and memory deficits [49, 50].

a(CHEBI:"okadaic acid") increases p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

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Annotations
MeSH
Hippocampus

a(CHEBI:"okadaic acid") decreases bp(GO:learning) View Subject | View Object

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Annotations
MeSH
Hippocampus

a(CHEBI:"okadaic acid") decreases bp(GO:memory) View Subject | View Object

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Annotations
MeSH
Hippocampus

Evidence f0e4df83ad
JSON

Studies in transgenic mice and in cell cultures have shown a connection between PP2A loss of function and tau hyper-phosphorylation and aggregation into PHF.

a(HBP:"paired helical filaments") negativeCorrelation act(p(FPLX:PPP2)) View Subject | View Object

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act(p(FPLX:PPP2)) negativeCorrelation p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) View Subject | View Object

Appears in Networks:

act(p(FPLX:PPP2)) negativeCorrelation a(HBP:"paired helical filaments") View Subject | View Object

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p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) negativeCorrelation act(p(FPLX:PPP2)) View Subject | View Object

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Evidence 4835545dfa
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PP2A is mainly pre- sent as a soluble protein in the cytosol but it is also encoun- tered in the nucleus, mitochondria, cytoskeleton, and mem- branes.

a(MESH:Mitochondria) association p(FPLX:PPP2) View Subject | View Object

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a(MESH:Cytosol) association p(FPLX:PPP2) View Subject | View Object

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a(MESH:"Cell Membrane") association p(FPLX:PPP2) View Subject | View Object

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a(MESH:"Cell Nucleus") association p(FPLX:PPP2) View Subject | View Object

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a(MESH:Cytoskeleton) association p(FPLX:PPP2) View Subject | View Object

Appears in Networks:

p(FPLX:PPP2) association a(MESH:Cytosol) View Subject | View Object

Appears in Networks:

p(FPLX:PPP2) association a(MESH:"Cell Nucleus") View Subject | View Object

Appears in Networks:

p(FPLX:PPP2) association a(MESH:Mitochondria) View Subject | View Object

Appears in Networks:

p(FPLX:PPP2) association a(MESH:Cytoskeleton) View Subject | View Object

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p(FPLX:PPP2) association a(MESH:"Cell Membrane") View Subject | View Object

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Evidence ea49ee3e17
JSON

Furthermore, phosphorylated PP2A C decorates neurofibrillary tangles.

a(MESH:"Neurofibrillary Tangles") association p(FPLX:PPP2C, pmod(Ph)) View Subject | View Object

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p(FPLX:PPP2C, pmod(Ph)) association a(MESH:"Neurofibrillary Tangles") View Subject | View Object

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Evidence 294263bda6
JSON

Within the brain, ACB55 (B55) is the major PP2A B iso- form and it binds to tau with high affinity both in in vitro protein-protein interaction paradigms and in cell cultures [36, 37].

a(MESH:Brain) association p(HGNC:PPP2R2A) View Subject | View Object

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p(HGNC:PPP2R2A) association a(MESH:Brain) View Subject | View Object

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Evidence fece5e3519
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Analyses of protein expression by using gel electrophore- sis and western blotting have shown not only a reduction of PP2A C expression levels but also a marked reduction of B55, thus indicating that PP2A impairment is the result of combined effects of different subunits [60].

p(FPLX:PPP2C) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HGNC:PPP2R2A) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:PPP2C) View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:PPP2R2A) View Subject | View Object

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Evidence f66551821e
JSON

So far, the most explored pathologies in which PP2A is implicated are cancer, and some viral and parasitic diseases [44]. More recently, PP2A has been investigated in FTLD linked to mutations in the tau gene [45].

p(FPLX:PPP2) association path(MESH:"Frontotemporal Dementia") View Subject | View Object

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p(FPLX:PPP2) association path(MESH:Neoplasms) View Subject | View Object

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path(MESH:"Frontotemporal Dementia") association p(FPLX:PPP2) View Subject | View Object

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path(MESH:Neoplasms) association p(FPLX:PPP2) View Subject | View Object

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Evidence 166f7f6289
JSON

Trans- genic mice with reduced PP2A activity show increased tau phosphorylation at Ser202/Thr205 and Ser42 [46].

act(p(FPLX:PPP2)) decreases p(HGNC:MAPT, pmod(Ph, Ser, 202), pmod(Ph, Thr, 205)) View Subject | View Object

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act(p(FPLX:PPP2)) decreases p(HGNC:MAPT, pmod(Ph, Ser, 242)) View Subject | View Object

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Evidence 9b7cfb123d
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Moreover, some tau kinases as cyclin- dependent kinase 5 (cdk5) and TPKI (thiamine pyrophos- phokinase 1)/GSK3 (glycogen synthase kinase 3) are acti- vated following PP2A inhibition in starved mice [51].

act(p(FPLX:PPP2)) decreases act(p(HGNC:CDK5)) View Subject | View Object

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act(p(FPLX:PPP2)) decreases act(p(HGNC:TPK1)) View Subject | View Object

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act(p(FPLX:PPP2)) decreases act(p(HGNC:GSK3B)) View Subject | View Object

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Evidence b4abce37a3
JSON

Several observations showing reduced PP2A activity by 30% in the frontal cortex in AD [55], were followed by a number of studies of PP2A mRNA and proteins.

act(p(FPLX:PPP2)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Frontal Lobe

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(FPLX:PPP2)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Frontal Lobe

Evidence 1ad7bcefd2
JSON

To sum up, PP2A activity is decreased in brain of AD, as revealed by using different approaches in different laboratories.

act(p(FPLX:PPP2)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

path(MESH:"Alzheimer Disease") negativeCorrelation act(p(FPLX:PPP2)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Brain

Evidence 6b8d457411
JSON

Decreased of PP2A, but not of other phosphatases, has also been observed in Down syndrome correlating with increased tau pathology.

p(FPLX:PPP2) negativeCorrelation path(MESH:"Down Syndrome") View Subject | View Object

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path(MESH:"Down Syndrome") negativeCorrelation p(FPLX:PPP2) View Subject | View Object

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Evidence 26c4acdad6
JSON

Car- boxyl methylation of the catalytic subunit is required for efficient in vivo assembly of the trimer C, A, and B [63-65]; a process that is balanced by the opposite actions of methyl- transferase type IV (PPMT) and the methylesterase PME-1 [66-70].

p(FPLX:PPP2C, pmod(Me)) increases complex(p(FPLX:"PPP2R_A"), p(FPLX:"PPP2R_B"), p(FPLX:PPP2C)) View Subject | View Object

Appears in Networks:

p(HGNC:ICMT) increases p(FPLX:PPP2C, pmod(Me)) View Subject | View Object

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p(HGNC:PPME1) decreases p(FPLX:PPP2C, pmod(Me)) View Subject | View Object

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Evidence 8fc139710a
JSON

PP2A C methylation at Leu309 is reduced in AD and this seems to contribute to PP2A C dysfunction by impairing the assembly of the trimer [77, 78].

p(FPLX:PPP2C, pmod(Me, Leu, 309)) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:

p(FPLX:PPP2C, pmod(Me, Leu, 309)) decreases complex(p(FPLX:"PPP2R_A"), p(FPLX:"PPP2R_B"), p(FPLX:PPP2C)) View Subject | View Object

Appears in Networks:

path(MESH:"Alzheimer Disease") negativeCorrelation p(FPLX:PPP2C, pmod(Me, Leu, 309)) View Subject | View Object

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Evidence 7eb9a48bd2
JSON

The other important post-translational modi- fication is phosphorylation of PP2A C at Tyr307 which in- hibits PP2A activity [74-76].

p(FPLX:PPP2C, pmod(Ph, Tyr, 307)) increases act(p(FPLX:PPP2)) View Subject | View Object

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Evidence 72c13e525a
JSON

High levels of PP2A C phosphorylated at Tyr307 have been reported in the entorhinal cortex, hippocampus and frontal cortex in AD compared to controls [81].

p(FPLX:PPP2C, pmod(Ph, Tyr, 307)) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Entorhinal Cortex
MeSH
Frontal Lobe
MeSH
Hippocampus

path(MESH:"Alzheimer Disease") positiveCorrelation p(FPLX:PPP2C, pmod(Ph, Tyr, 307)) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Entorhinal Cortex
MeSH
Frontal Lobe
MeSH
Hippocampus

Evidence 1c3d28070b
JSON

Complementing these findings, immu- nohistochemical and western blot studies have shown re- duced expression of PPMT [77], and up-regulation of the PP2A inhibitors I 1 and I 2 in AD cases [79, 80].

p(HGNC:ANP32A) decreases act(p(FPLX:PPP2)) View Subject | View Object

Appears in Networks:

p(HGNC:ANP32A) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HGNC:ICMT) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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p(HGNC:SET) decreases act(p(FPLX:PPP2)) View Subject | View Object

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p(HGNC:SET) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

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path(MESH:"Alzheimer Disease") negativeCorrelation p(HGNC:ICMT) View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:ANP32A) View Subject | View Object

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path(MESH:"Alzheimer Disease") positiveCorrelation p(HGNC:SET) View Subject | View Object

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Evidence 678d10ee72
JSON

The excessive accumulation of phosphate groups in tau is associated with its altered capacity in promoting microtubule assembly and stability [4-6].

p(HGNC:MAPT, pmod(HBP:hyperphosphorylation)) decreases bp(GO:"microtubule polymerization") View Subject | View Object

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Evidence 5991cd4f9e
JSON

Decreased mRNA levels of PP2A C have been reported in the CA3 region of AD hippocampus by in situ RNA hybridisation [56]. Moreover, microarray RNA analysis carried out to compare the expression of more than 7,000 gene in the amygdala, cingulate cortex, striatum and cerebellum dis- closed down-regulation of the catalytic subunit PP2A C in AD [57]. This has been further corroborated by quantitative TaqMan PCR showing reduced PP2A C mRNA expression levels in the hippocampus, but not in the frontal cortex, in AD cases with disease progression Fig. (1).

path(MESH:"Alzheimer Disease") negativeCorrelation r(HGNC:PPP2CA) View Subject | View Object

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Annotations
MeSH
CA3 Region, Hippocampal

path(MESH:"Alzheimer Disease") negativeCorrelation r(HGNC:PPP2CB) View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA3 Region, Hippocampal

r(HGNC:PPP2CA) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA3 Region, Hippocampal

r(HGNC:PPP2CB) negativeCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
MeSH
CA3 Region, Hippocampal

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