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Prion protein and Abeta-related synaptic toxicity impairment.

Calella AM, Farinelli M, Nuvolone M, Mirante O, Moos R, Falsig J, Mansuy IM, Aguzzi A - EMBO Mol Med (2010)

Bottom Line: Numerous studies have shown that Abeta oligomers, both synthetic and derived from cultures and AD brains, potently impair synaptic structure and functions.The cellular prion protein (PrP(C)) was proposed to mediate this effect.These findings challenge the role of PrP(C) as a mediator of Abeta toxicity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuropathology, University Hospital Zürich, Zürich, Switzerland.

ABSTRACT
Alzheimer's disease (AD), the most common neurodegenerative disorder, goes along with extracellular amyloid-beta (Abeta) deposits. The cognitive decline observed during AD progression correlates with damaged spines, dendrites and synapses in hippocampus and cortex. Numerous studies have shown that Abeta oligomers, both synthetic and derived from cultures and AD brains, potently impair synaptic structure and functions. The cellular prion protein (PrP(C)) was proposed to mediate this effect. We report that ablation or overexpression of PrP(C) had no effect on the impairment of hippocampal synaptic plasticity in a transgenic model of AD. These findings challenge the role of PrP(C) as a mediator of Abeta toxicity.

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Related in: MedlinePlus

Analysis of 4-month-old APPPS1+ mice with supraphysiological levels of PrPCPercentage of strain-specific microsatellites in APPPS1+tga20tg/−Prnp+/o (n = 6) and APPPS1+tga20−/−Prnp+/o (n = 4) mice is displayed by box plot. No significant difference in the genetic background of the two mouse strains was detected (Mann–Whitney U-test, two-tailed, p > 0.05).At 4 months of age, slices of both APPPS1+tga20tg/−Prnp+/o (n = 6) and APPPS1+tga20−/−Prnp+/o mice (n = 4) displayed reduced LTP when compared to Prnp+/+ mice (n = 7); LTP mean ± SEMfrom Fig 1A represented as grey ribbon. Basal synaptic transmission was normal as indicated by normal input–output curve (stimulus intensity vs. fEPSP slope). All error bars: standard errors of the mean.APP expression and processing by secretases were similar in 4-month-old APPPS1+tga20tg/−Prnp+/o and APPPS1+tga20−/−Prnp+/o mice. Left panel: representative SDS–PAGE followed by immunoblotting using an APP C-terminal antibody detecting full-length APP and αβ-CTF; actin was used as loading control. Right panel: quantitation of chemiluminescence for APP, α-CTF and β-CTF.TRIS-soluble (left panel), detergent-soluble (middle panel) and insoluble (right panel) human Aβ42 levels as assessed by ELISA. Each symbol denotes one individual mouse.
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fig03: Analysis of 4-month-old APPPS1+ mice with supraphysiological levels of PrPCPercentage of strain-specific microsatellites in APPPS1+tga20tg/−Prnp+/o (n = 6) and APPPS1+tga20−/−Prnp+/o (n = 4) mice is displayed by box plot. No significant difference in the genetic background of the two mouse strains was detected (Mann–Whitney U-test, two-tailed, p > 0.05).At 4 months of age, slices of both APPPS1+tga20tg/−Prnp+/o (n = 6) and APPPS1+tga20−/−Prnp+/o mice (n = 4) displayed reduced LTP when compared to Prnp+/+ mice (n = 7); LTP mean ± SEMfrom Fig 1A represented as grey ribbon. Basal synaptic transmission was normal as indicated by normal input–output curve (stimulus intensity vs. fEPSP slope). All error bars: standard errors of the mean.APP expression and processing by secretases were similar in 4-month-old APPPS1+tga20tg/−Prnp+/o and APPPS1+tga20−/−Prnp+/o mice. Left panel: representative SDS–PAGE followed by immunoblotting using an APP C-terminal antibody detecting full-length APP and αβ-CTF; actin was used as loading control. Right panel: quantitation of chemiluminescence for APP, α-CTF and β-CTF.TRIS-soluble (left panel), detergent-soluble (middle panel) and insoluble (right panel) human Aβ42 levels as assessed by ELISA. Each symbol denotes one individual mouse.

Mentions: To formally discriminate between PrPC-dependent effect and potential confounders residing on Mmu2, we reintroduced PrPC into APPPS1+Prnpo/o mice via crosses to tga20 mice (Fischer et al, 1996) that carry a Prnp minigene on Mmu17 (Zabel et al, 2009) and overexpress PrPC about fourfold (Fig S3). LTP was again affected in 4-month-old APPPS1+tga20tg/−Prnpo/o (127.84 ± 12.61%; n = 4) and APPPS1+tga20−/−Prnpo/o littermates (106.56 ± 5.46%; n = 5; p = 0.137; Fig 2A). The genome-wide microsatellite patterns of these two groups of mice were indistinguishable even when Mmu2 markers were included (129/Sv-specific markers: 61.0 ± 2.1 vs. 61.7 ± 3.9, respectively; p > 0.05; Fig 2B), indicating that any contribution by genetic confounders to the phenotype is unlikely. To further explore the impact of supraphysiological levels on PrPC in LTP, we analyzed APPPS1+tga20tg/−Prnp+/o which overexpress ca. sevenfold PrPC (Fig S3) and APPPS1+tga20−/−Prnp+/o littermates. These two groups of mice shared similar genomic microsatellite patterns (Fig 3A). At 4 months of age, LTP was significantly reduced in both APPPS1+tga20tg/−Prnp+/o and APPPS1+tga20−/−Prnp+/o littermates (149.41 ± 11.81%, n = 6 vs. 121.56 ± 11.65%, respectively; n = 4; Fig 3B). Expression of the tga20 allele showed a tendency towards improved LTP that was not statistically significant, without altering APP catabolites and soluble and insoluble Aβ42 (Fig 3C and D). Therefore, PrPC overexpression did not enhance Aβ-mediated LTP impairment; if anything, it may have marginally antagonized it.


Prion protein and Abeta-related synaptic toxicity impairment.

Calella AM, Farinelli M, Nuvolone M, Mirante O, Moos R, Falsig J, Mansuy IM, Aguzzi A - EMBO Mol Med (2010)

Analysis of 4-month-old APPPS1+ mice with supraphysiological levels of PrPCPercentage of strain-specific microsatellites in APPPS1+tga20tg/−Prnp+/o (n = 6) and APPPS1+tga20−/−Prnp+/o (n = 4) mice is displayed by box plot. No significant difference in the genetic background of the two mouse strains was detected (Mann–Whitney U-test, two-tailed, p > 0.05).At 4 months of age, slices of both APPPS1+tga20tg/−Prnp+/o (n = 6) and APPPS1+tga20−/−Prnp+/o mice (n = 4) displayed reduced LTP when compared to Prnp+/+ mice (n = 7); LTP mean ± SEMfrom Fig 1A represented as grey ribbon. Basal synaptic transmission was normal as indicated by normal input–output curve (stimulus intensity vs. fEPSP slope). All error bars: standard errors of the mean.APP expression and processing by secretases were similar in 4-month-old APPPS1+tga20tg/−Prnp+/o and APPPS1+tga20−/−Prnp+/o mice. Left panel: representative SDS–PAGE followed by immunoblotting using an APP C-terminal antibody detecting full-length APP and αβ-CTF; actin was used as loading control. Right panel: quantitation of chemiluminescence for APP, α-CTF and β-CTF.TRIS-soluble (left panel), detergent-soluble (middle panel) and insoluble (right panel) human Aβ42 levels as assessed by ELISA. Each symbol denotes one individual mouse.
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Related In: Results  -  Collection

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fig03: Analysis of 4-month-old APPPS1+ mice with supraphysiological levels of PrPCPercentage of strain-specific microsatellites in APPPS1+tga20tg/−Prnp+/o (n = 6) and APPPS1+tga20−/−Prnp+/o (n = 4) mice is displayed by box plot. No significant difference in the genetic background of the two mouse strains was detected (Mann–Whitney U-test, two-tailed, p > 0.05).At 4 months of age, slices of both APPPS1+tga20tg/−Prnp+/o (n = 6) and APPPS1+tga20−/−Prnp+/o mice (n = 4) displayed reduced LTP when compared to Prnp+/+ mice (n = 7); LTP mean ± SEMfrom Fig 1A represented as grey ribbon. Basal synaptic transmission was normal as indicated by normal input–output curve (stimulus intensity vs. fEPSP slope). All error bars: standard errors of the mean.APP expression and processing by secretases were similar in 4-month-old APPPS1+tga20tg/−Prnp+/o and APPPS1+tga20−/−Prnp+/o mice. Left panel: representative SDS–PAGE followed by immunoblotting using an APP C-terminal antibody detecting full-length APP and αβ-CTF; actin was used as loading control. Right panel: quantitation of chemiluminescence for APP, α-CTF and β-CTF.TRIS-soluble (left panel), detergent-soluble (middle panel) and insoluble (right panel) human Aβ42 levels as assessed by ELISA. Each symbol denotes one individual mouse.
Mentions: To formally discriminate between PrPC-dependent effect and potential confounders residing on Mmu2, we reintroduced PrPC into APPPS1+Prnpo/o mice via crosses to tga20 mice (Fischer et al, 1996) that carry a Prnp minigene on Mmu17 (Zabel et al, 2009) and overexpress PrPC about fourfold (Fig S3). LTP was again affected in 4-month-old APPPS1+tga20tg/−Prnpo/o (127.84 ± 12.61%; n = 4) and APPPS1+tga20−/−Prnpo/o littermates (106.56 ± 5.46%; n = 5; p = 0.137; Fig 2A). The genome-wide microsatellite patterns of these two groups of mice were indistinguishable even when Mmu2 markers were included (129/Sv-specific markers: 61.0 ± 2.1 vs. 61.7 ± 3.9, respectively; p > 0.05; Fig 2B), indicating that any contribution by genetic confounders to the phenotype is unlikely. To further explore the impact of supraphysiological levels on PrPC in LTP, we analyzed APPPS1+tga20tg/−Prnp+/o which overexpress ca. sevenfold PrPC (Fig S3) and APPPS1+tga20−/−Prnp+/o littermates. These two groups of mice shared similar genomic microsatellite patterns (Fig 3A). At 4 months of age, LTP was significantly reduced in both APPPS1+tga20tg/−Prnp+/o and APPPS1+tga20−/−Prnp+/o littermates (149.41 ± 11.81%, n = 6 vs. 121.56 ± 11.65%, respectively; n = 4; Fig 3B). Expression of the tga20 allele showed a tendency towards improved LTP that was not statistically significant, without altering APP catabolites and soluble and insoluble Aβ42 (Fig 3C and D). Therefore, PrPC overexpression did not enhance Aβ-mediated LTP impairment; if anything, it may have marginally antagonized it.

Bottom Line: Numerous studies have shown that Abeta oligomers, both synthetic and derived from cultures and AD brains, potently impair synaptic structure and functions.The cellular prion protein (PrP(C)) was proposed to mediate this effect.These findings challenge the role of PrP(C) as a mediator of Abeta toxicity.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuropathology, University Hospital Zürich, Zürich, Switzerland.

ABSTRACT
Alzheimer's disease (AD), the most common neurodegenerative disorder, goes along with extracellular amyloid-beta (Abeta) deposits. The cognitive decline observed during AD progression correlates with damaged spines, dendrites and synapses in hippocampus and cortex. Numerous studies have shown that Abeta oligomers, both synthetic and derived from cultures and AD brains, potently impair synaptic structure and functions. The cellular prion protein (PrP(C)) was proposed to mediate this effect. We report that ablation or overexpression of PrP(C) had no effect on the impairment of hippocampal synaptic plasticity in a transgenic model of AD. These findings challenge the role of PrP(C) as a mediator of Abeta toxicity.

Show MeSH
Related in: MedlinePlus