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Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits.

Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E, Pierre P, Cavener DR, Klann E - Nat. Neurosci. (2013)

Bottom Line: Expression of long-lasting synaptic plasticity and long-term memory requires protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2 α-subunit (eIF2α).Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and defects in spatial memory exhibited by the Alzheimer's disease model mice.Our findings implicate aberrant eIF2α phosphorylation as a previously unidentified molecular mechanism underlying Alzheimer's disease-related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for treatment of individuals with Alzheimer's disease.

View Article: PubMed Central - PubMed

Affiliation: Center for Neural Science, New York University, New York, New York, USA.

ABSTRACT
Expression of long-lasting synaptic plasticity and long-term memory requires protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2 α-subunit (eIF2α). Elevated phosphorylation of eIF2α has been observed in the brains of Alzheimer's disease patients and Alzheimer's disease model mice. Therefore, we tested whether suppressing eIF2α kinases could alleviate synaptic plasticity and memory deficits in Alzheimer's disease model mice. Genetic deletion of eIF2α kinase PERK prevented enhanced phosphorylation of eIF2α and deficits in protein synthesis, synaptic plasticity and spatial memory in mice that express familial Alzheimer's disease-related mutations in APP and PSEN1. Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and defects in spatial memory exhibited by the Alzheimer's disease model mice. Our findings implicate aberrant eIF2α phosphorylation as a previously unidentified molecular mechanism underlying Alzheimer's disease-related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for treatment of individuals with Alzheimer's disease.

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Generation of AD model mice with reduced PERK-eIF2α signaling(a) Diagram depicting the creation of mice with AD-associated transgenes and reduced PERK/eIF2α signaling. (b) eIF2α phosphorylation was reduced in hippocampal area CA1 of APP/PS1/PERK cKO mice compared to the increased levels of eIF2α phosphosphorylation in APP/PS1 mice, which was correlated with the expression of PERK (c). n=10 for APP/PS1/PERK cKO, n=6 the other three groups. (d) Representative Western blot showing that de novo protein synthesis (assayed by SUnSET) was reduced in APP/PS1 mice compared to WT littermates. In addition, de novo protein synthesis in PERK cKO and APP/PERK cKO mice was not different from WT mice. (e) Cumulative data showing densitometric analysis of experiments in panel d. n=4. *p<0.05. (f) Elevated levels of ATF4 in APP/PS1 mice were reduced to WT levels in APP/PS1/PERK cKO mice. Western blots were performed on tissue from area CA1 of the hippocampus. n=10. All data for the densitometric analysis of the Western blots were presented as mean ± SEM. *p< 0.05, **p< 0.01, ***p<0.001. Full-length blots/gels are presented in Supplementary Figure 7.
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Figure 3: Generation of AD model mice with reduced PERK-eIF2α signaling(a) Diagram depicting the creation of mice with AD-associated transgenes and reduced PERK/eIF2α signaling. (b) eIF2α phosphorylation was reduced in hippocampal area CA1 of APP/PS1/PERK cKO mice compared to the increased levels of eIF2α phosphosphorylation in APP/PS1 mice, which was correlated with the expression of PERK (c). n=10 for APP/PS1/PERK cKO, n=6 the other three groups. (d) Representative Western blot showing that de novo protein synthesis (assayed by SUnSET) was reduced in APP/PS1 mice compared to WT littermates. In addition, de novo protein synthesis in PERK cKO and APP/PERK cKO mice was not different from WT mice. (e) Cumulative data showing densitometric analysis of experiments in panel d. n=4. *p<0.05. (f) Elevated levels of ATF4 in APP/PS1 mice were reduced to WT levels in APP/PS1/PERK cKO mice. Western blots were performed on tissue from area CA1 of the hippocampus. n=10. All data for the densitometric analysis of the Western blots were presented as mean ± SEM. *p< 0.05, **p< 0.01, ***p<0.001. Full-length blots/gels are presented in Supplementary Figure 7.

Mentions: We then proceeded to generate a mutant mouse line that expressed both APPswe/PS1ΔE9 and homozygous Cre PERK−/−flox transgenes (APP/PS1/PERK cKO). The breeding strategy involved two stages: generation of female mice with the APPswe/PS1ΔE9 and heterozygous Cre PERK+/−flox transgenes followed by breeding with male heterozygous PERK+/−flox mice. All mice generated for these experiments were aged for 10–12 months, an age when APP/PS1 mice reliably display synaptic dysfunction and memory deficits20–21. After approximately 18 months of breeding we obtained a sufficient number of aged APP/PS1/PERK cKO mutant mice (APPswe/PS1ΔE9 and Cre PERK−/−flox), along with three other littermate groups for experiments (Fig. 3a): WT (Cre only), APP/PS1 (APPswe/PS1ΔE9), and PERK cKO (Cre PERK−/−flox).


Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits.

Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E, Pierre P, Cavener DR, Klann E - Nat. Neurosci. (2013)

Generation of AD model mice with reduced PERK-eIF2α signaling(a) Diagram depicting the creation of mice with AD-associated transgenes and reduced PERK/eIF2α signaling. (b) eIF2α phosphorylation was reduced in hippocampal area CA1 of APP/PS1/PERK cKO mice compared to the increased levels of eIF2α phosphosphorylation in APP/PS1 mice, which was correlated with the expression of PERK (c). n=10 for APP/PS1/PERK cKO, n=6 the other three groups. (d) Representative Western blot showing that de novo protein synthesis (assayed by SUnSET) was reduced in APP/PS1 mice compared to WT littermates. In addition, de novo protein synthesis in PERK cKO and APP/PERK cKO mice was not different from WT mice. (e) Cumulative data showing densitometric analysis of experiments in panel d. n=4. *p<0.05. (f) Elevated levels of ATF4 in APP/PS1 mice were reduced to WT levels in APP/PS1/PERK cKO mice. Western blots were performed on tissue from area CA1 of the hippocampus. n=10. All data for the densitometric analysis of the Western blots were presented as mean ± SEM. *p< 0.05, **p< 0.01, ***p<0.001. Full-length blots/gels are presented in Supplementary Figure 7.
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Figure 3: Generation of AD model mice with reduced PERK-eIF2α signaling(a) Diagram depicting the creation of mice with AD-associated transgenes and reduced PERK/eIF2α signaling. (b) eIF2α phosphorylation was reduced in hippocampal area CA1 of APP/PS1/PERK cKO mice compared to the increased levels of eIF2α phosphosphorylation in APP/PS1 mice, which was correlated with the expression of PERK (c). n=10 for APP/PS1/PERK cKO, n=6 the other three groups. (d) Representative Western blot showing that de novo protein synthesis (assayed by SUnSET) was reduced in APP/PS1 mice compared to WT littermates. In addition, de novo protein synthesis in PERK cKO and APP/PERK cKO mice was not different from WT mice. (e) Cumulative data showing densitometric analysis of experiments in panel d. n=4. *p<0.05. (f) Elevated levels of ATF4 in APP/PS1 mice were reduced to WT levels in APP/PS1/PERK cKO mice. Western blots were performed on tissue from area CA1 of the hippocampus. n=10. All data for the densitometric analysis of the Western blots were presented as mean ± SEM. *p< 0.05, **p< 0.01, ***p<0.001. Full-length blots/gels are presented in Supplementary Figure 7.
Mentions: We then proceeded to generate a mutant mouse line that expressed both APPswe/PS1ΔE9 and homozygous Cre PERK−/−flox transgenes (APP/PS1/PERK cKO). The breeding strategy involved two stages: generation of female mice with the APPswe/PS1ΔE9 and heterozygous Cre PERK+/−flox transgenes followed by breeding with male heterozygous PERK+/−flox mice. All mice generated for these experiments were aged for 10–12 months, an age when APP/PS1 mice reliably display synaptic dysfunction and memory deficits20–21. After approximately 18 months of breeding we obtained a sufficient number of aged APP/PS1/PERK cKO mutant mice (APPswe/PS1ΔE9 and Cre PERK−/−flox), along with three other littermate groups for experiments (Fig. 3a): WT (Cre only), APP/PS1 (APPswe/PS1ΔE9), and PERK cKO (Cre PERK−/−flox).

Bottom Line: Expression of long-lasting synaptic plasticity and long-term memory requires protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2 α-subunit (eIF2α).Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and defects in spatial memory exhibited by the Alzheimer's disease model mice.Our findings implicate aberrant eIF2α phosphorylation as a previously unidentified molecular mechanism underlying Alzheimer's disease-related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for treatment of individuals with Alzheimer's disease.

View Article: PubMed Central - PubMed

Affiliation: Center for Neural Science, New York University, New York, New York, USA.

ABSTRACT
Expression of long-lasting synaptic plasticity and long-term memory requires protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2 α-subunit (eIF2α). Elevated phosphorylation of eIF2α has been observed in the brains of Alzheimer's disease patients and Alzheimer's disease model mice. Therefore, we tested whether suppressing eIF2α kinases could alleviate synaptic plasticity and memory deficits in Alzheimer's disease model mice. Genetic deletion of eIF2α kinase PERK prevented enhanced phosphorylation of eIF2α and deficits in protein synthesis, synaptic plasticity and spatial memory in mice that express familial Alzheimer's disease-related mutations in APP and PSEN1. Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and defects in spatial memory exhibited by the Alzheimer's disease model mice. Our findings implicate aberrant eIF2α phosphorylation as a previously unidentified molecular mechanism underlying Alzheimer's disease-related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for treatment of individuals with Alzheimer's disease.

Show MeSH
Related in: MedlinePlus