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FMRP mediates mGluR5-dependent translation of amyloid precursor protein.

Westmark CJ, Malter JS - PLoS Biol. (2007)

Bottom Line: Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Abeta) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission.APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment.Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, Wisconsin, United States of America. westmark@facstaff.wisc.edu

ABSTRACT
Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Abeta) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expression is lost in fragile X syndrome. Here we show that FMRP binds to the coding region of APP mRNA at a guanine-rich, G-quartet-like sequence. Stimulation of cortical synaptoneurosomes or primary neuronal cells with the metabotropic glutamate receptor agonist DHPG increased APP translation in wild-type but not fmr-1 knockout samples. APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment. Soluble Abeta40 or Abeta42 levels were significantly higher in multiple strains of fmr-1 knockout mice compared to wild-type controls. Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome.

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Increased Aβ40 and Aβ42 Levels in fmr-1 KO Mice(A) Soluble brain lysates from 1-y-old WT and fmr-1 KO mice (FVB strain) analyzed by ELISA and plotted as a percentage of soluble Aβ compared to WT controls. Student t-tests: p = 0.06 (Aβ40) and p = 0.001 (Aβ42).(B) GnHCl-soluble brain lysates from 1-y-old WT and fmr-1 KO mice (C57BL/6 strain) analyzed by ELISA and plotted as a percentage of GnHCl-soluble Aβ compared to WT controls. Student t-tests: p < 0.001 (Aβ40) and p = 0.39 (Aβ42).
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pbio-0050052-g008: Increased Aβ40 and Aβ42 Levels in fmr-1 KO Mice(A) Soluble brain lysates from 1-y-old WT and fmr-1 KO mice (FVB strain) analyzed by ELISA and plotted as a percentage of soluble Aβ compared to WT controls. Student t-tests: p = 0.06 (Aβ40) and p = 0.001 (Aβ42).(B) GnHCl-soluble brain lysates from 1-y-old WT and fmr-1 KO mice (C57BL/6 strain) analyzed by ELISA and plotted as a percentage of GnHCl-soluble Aβ compared to WT controls. Student t-tests: p < 0.001 (Aβ40) and p = 0.39 (Aβ42).

Mentions: Increased translation of APP provides more targets for cleavage by β- and γ-secretases. Therefore, we would expect fmr-1 KO mice to have exacerbated Aβ production with aging. Right-brain hemispheres from middle-aged FVB mice (11–13 mo old) were homogenized in protein extraction buffer containing 1% Triton X-100 and protease inhibitors and the soluble material was analyzed by enzyme-linked immunosorbent assay (ELISA) for Aβ40 and Aβ42. The fmr-1 KO mouse brain contained 1.6 times more Aβ40 and 2.5 times more Aβ42 than WT controls (Figure 8A). We also tested Aβ40/42 levels in C57BL/6 mice (12–14 mo old) to ensure that this was not a strain-specific event. We did not observe an increase in soluble Aβ40 or Aβ42 levels in fmr-1 KO C57BL/6 brain samples (unpublished data), but guanidine-soluble fractions showed a 2.8-fold increase in Aβ40 and a 1.2-fold increase in Aβ42 (Figure 8B). Therefore, the brains of two distinct murine strains lacking fmr-1 both showed increased APP and accumulated pathogenic Aβ species over time.


FMRP mediates mGluR5-dependent translation of amyloid precursor protein.

Westmark CJ, Malter JS - PLoS Biol. (2007)

Increased Aβ40 and Aβ42 Levels in fmr-1 KO Mice(A) Soluble brain lysates from 1-y-old WT and fmr-1 KO mice (FVB strain) analyzed by ELISA and plotted as a percentage of soluble Aβ compared to WT controls. Student t-tests: p = 0.06 (Aβ40) and p = 0.001 (Aβ42).(B) GnHCl-soluble brain lysates from 1-y-old WT and fmr-1 KO mice (C57BL/6 strain) analyzed by ELISA and plotted as a percentage of GnHCl-soluble Aβ compared to WT controls. Student t-tests: p < 0.001 (Aβ40) and p = 0.39 (Aβ42).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC1808499&req=5

pbio-0050052-g008: Increased Aβ40 and Aβ42 Levels in fmr-1 KO Mice(A) Soluble brain lysates from 1-y-old WT and fmr-1 KO mice (FVB strain) analyzed by ELISA and plotted as a percentage of soluble Aβ compared to WT controls. Student t-tests: p = 0.06 (Aβ40) and p = 0.001 (Aβ42).(B) GnHCl-soluble brain lysates from 1-y-old WT and fmr-1 KO mice (C57BL/6 strain) analyzed by ELISA and plotted as a percentage of GnHCl-soluble Aβ compared to WT controls. Student t-tests: p < 0.001 (Aβ40) and p = 0.39 (Aβ42).
Mentions: Increased translation of APP provides more targets for cleavage by β- and γ-secretases. Therefore, we would expect fmr-1 KO mice to have exacerbated Aβ production with aging. Right-brain hemispheres from middle-aged FVB mice (11–13 mo old) were homogenized in protein extraction buffer containing 1% Triton X-100 and protease inhibitors and the soluble material was analyzed by enzyme-linked immunosorbent assay (ELISA) for Aβ40 and Aβ42. The fmr-1 KO mouse brain contained 1.6 times more Aβ40 and 2.5 times more Aβ42 than WT controls (Figure 8A). We also tested Aβ40/42 levels in C57BL/6 mice (12–14 mo old) to ensure that this was not a strain-specific event. We did not observe an increase in soluble Aβ40 or Aβ42 levels in fmr-1 KO C57BL/6 brain samples (unpublished data), but guanidine-soluble fractions showed a 2.8-fold increase in Aβ40 and a 1.2-fold increase in Aβ42 (Figure 8B). Therefore, the brains of two distinct murine strains lacking fmr-1 both showed increased APP and accumulated pathogenic Aβ species over time.

Bottom Line: Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Abeta) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission.APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment.Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Waisman Center for Developmental Disabilities, University of Wisconsin, Madison, Wisconsin, United States of America. westmark@facstaff.wisc.edu

ABSTRACT
Amyloid precursor protein (APP) facilitates synapse formation in the developing brain, while beta-amyloid (Abeta) accumulation, which is associated with Alzheimer disease, results in synaptic loss and impaired neurotransmission. Fragile X mental retardation protein (FMRP) is a cytoplasmic mRNA binding protein whose expression is lost in fragile X syndrome. Here we show that FMRP binds to the coding region of APP mRNA at a guanine-rich, G-quartet-like sequence. Stimulation of cortical synaptoneurosomes or primary neuronal cells with the metabotropic glutamate receptor agonist DHPG increased APP translation in wild-type but not fmr-1 knockout samples. APP mRNA coimmunoprecipitated with FMRP in resting synaptoneurosomes, but the interaction was lost shortly after DHPG treatment. Soluble Abeta40 or Abeta42 levels were significantly higher in multiple strains of fmr-1 knockout mice compared to wild-type controls. Our data indicate that postsynaptic FMRP binds to and regulates the translation of APP mRNA through metabotropic glutamate receptor activation and suggests a possible link between Alzheimer disease and fragile X syndrome.

Show MeSH
Related in: MedlinePlus