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Alzheimer-related decrease in CYFIP2 links amyloid production to tau hyperphosphorylation and memory loss

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ABSTRACT

CYFIP2 is thought to regulate mRNA translation at synapses. Tiwari et al. reveal reduced CYFIP2 expression in post-mortem Alzheimer’s disease brains, and show that CYFIP2 reduction in mice causes abnormal amyloid production, tau hyperphosphorylation, and spatial memory loss. CYFIP2 could represent a molecular ‘hub’ with potential as a therapeutic target in Alzheimer’s disease.

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Reduced CYFIP2 expression leads to increased αCaMKII expression at protein but not mRNA level, and increased tau phosphorylation in the hippocampus. (A) Representative western blots. (B) Quantification showed that αCaMKII protein expression is significantly upregulated ∼2-fold in hippocampal synaptosomes of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). (C) Quantitative PCR analysis showed that Camk2a/αCaMKII mRNA levels are not elevated in hippocampus of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). (D) Representative western blots. (E) Quantification showed an ∼50% increase in phosphorylation of tau at serine-214 in hippocampal synaptosomes of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). (F) Quantification showed that total levels of tau did not differ in hippocampal synaptosomes of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). Means ± SEM are shown. *P < 0.05, **P < 0.01.
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aww205-F4: Reduced CYFIP2 expression leads to increased αCaMKII expression at protein but not mRNA level, and increased tau phosphorylation in the hippocampus. (A) Representative western blots. (B) Quantification showed that αCaMKII protein expression is significantly upregulated ∼2-fold in hippocampal synaptosomes of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). (C) Quantitative PCR analysis showed that Camk2a/αCaMKII mRNA levels are not elevated in hippocampus of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). (D) Representative western blots. (E) Quantification showed an ∼50% increase in phosphorylation of tau at serine-214 in hippocampal synaptosomes of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). (F) Quantification showed that total levels of tau did not differ in hippocampal synaptosomes of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). Means ± SEM are shown. *P < 0.05, **P < 0.01.

Mentions: Like App mRNA, Camk2a (αCaMKII) mRNA is locally translated in an FMRP-dependent manner (Napoli et al., 2008). Moreover, recent studies have suggested that increased αCaMKII activity contributes to tau hyperphosphorylation in Alzheimer’s disease (Ghosh and Giese, 2015). Therefore, we studied whether reduced CYFIP2 expression affects αCaMKII expression in the hippocampus. Western blot analysis showed that αCaMKII protein expression was significantly elevated ∼2.5-fold in hippocampal synaptosomes in Cyfip2+/− mice in comparison to wild-type littermates (t = 3.05, P < 0.05; Fig. 4A and B). This effect was not observed in total hippocampal lysates (Supplementary Fig. 7A and B). This is likely due to a dilution of synaptic signal in total lysates as αCaMKII is also highly expressed in somata and dendrites of hippocampal neurons (Giese et al., 1998). Quantitative PCR analysis showed that the Camk2a/αCaMKII mRNA expression level was not altered in the hippocampus of Cyfip2+/− mutants (t = 0.39, P = 70; Fig. 4C). This result suggests that CYFIP2 regulates translation of Camk2a/αCaMKII mRNA. We tested also whether the increased αCaMKII protein expression correlates with altered tau phosphorylation at serine-214 (S214), a site that is phosphorylated by CaMKII, and one of the key sites that are hyperphosphorylated in Alzheimer’s disease (Lee et al., 2001). The expression of total tau was not altered in Cyfip2+/− mutants in comparison to wild-type littermates (t = 0.31, P = 076; Fig. 4D and F). However, phosphorylation of tau at S214 was significantly increased by ∼60% in Cyfip2+/− mice in comparison to wild-type littermates (t = 3.63, P < 0.01; Fig. 4D and E).Figure 4


Alzheimer-related decrease in CYFIP2 links amyloid production to tau hyperphosphorylation and memory loss
Reduced CYFIP2 expression leads to increased αCaMKII expression at protein but not mRNA level, and increased tau phosphorylation in the hippocampus. (A) Representative western blots. (B) Quantification showed that αCaMKII protein expression is significantly upregulated ∼2-fold in hippocampal synaptosomes of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). (C) Quantitative PCR analysis showed that Camk2a/αCaMKII mRNA levels are not elevated in hippocampus of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). (D) Representative western blots. (E) Quantification showed an ∼50% increase in phosphorylation of tau at serine-214 in hippocampal synaptosomes of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). (F) Quantification showed that total levels of tau did not differ in hippocampal synaptosomes of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). Means ± SEM are shown. *P < 0.05, **P < 0.01.
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aww205-F4: Reduced CYFIP2 expression leads to increased αCaMKII expression at protein but not mRNA level, and increased tau phosphorylation in the hippocampus. (A) Representative western blots. (B) Quantification showed that αCaMKII protein expression is significantly upregulated ∼2-fold in hippocampal synaptosomes of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). (C) Quantitative PCR analysis showed that Camk2a/αCaMKII mRNA levels are not elevated in hippocampus of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). (D) Representative western blots. (E) Quantification showed an ∼50% increase in phosphorylation of tau at serine-214 in hippocampal synaptosomes of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). (F) Quantification showed that total levels of tau did not differ in hippocampal synaptosomes of Cyfip2+/− mice (black bar) in comparison to wild-type littermates (grey bar; n = 8 per genotype). Means ± SEM are shown. *P < 0.05, **P < 0.01.
Mentions: Like App mRNA, Camk2a (αCaMKII) mRNA is locally translated in an FMRP-dependent manner (Napoli et al., 2008). Moreover, recent studies have suggested that increased αCaMKII activity contributes to tau hyperphosphorylation in Alzheimer’s disease (Ghosh and Giese, 2015). Therefore, we studied whether reduced CYFIP2 expression affects αCaMKII expression in the hippocampus. Western blot analysis showed that αCaMKII protein expression was significantly elevated ∼2.5-fold in hippocampal synaptosomes in Cyfip2+/− mice in comparison to wild-type littermates (t = 3.05, P < 0.05; Fig. 4A and B). This effect was not observed in total hippocampal lysates (Supplementary Fig. 7A and B). This is likely due to a dilution of synaptic signal in total lysates as αCaMKII is also highly expressed in somata and dendrites of hippocampal neurons (Giese et al., 1998). Quantitative PCR analysis showed that the Camk2a/αCaMKII mRNA expression level was not altered in the hippocampus of Cyfip2+/− mutants (t = 0.39, P = 70; Fig. 4C). This result suggests that CYFIP2 regulates translation of Camk2a/αCaMKII mRNA. We tested also whether the increased αCaMKII protein expression correlates with altered tau phosphorylation at serine-214 (S214), a site that is phosphorylated by CaMKII, and one of the key sites that are hyperphosphorylated in Alzheimer’s disease (Lee et al., 2001). The expression of total tau was not altered in Cyfip2+/− mutants in comparison to wild-type littermates (t = 0.31, P = 076; Fig. 4D and F). However, phosphorylation of tau at S214 was significantly increased by ∼60% in Cyfip2+/− mice in comparison to wild-type littermates (t = 3.63, P < 0.01; Fig. 4D and E).Figure 4

View Article: PubMed Central - PubMed

ABSTRACT

CYFIP2 is thought to regulate mRNA translation at synapses. Tiwari et al. reveal reduced CYFIP2 expression in post-mortem Alzheimer&rsquo;s disease brains, and show that CYFIP2 reduction in mice causes abnormal amyloid production, tau hyperphosphorylation, and spatial memory loss. CYFIP2 could represent a molecular &lsquo;hub&rsquo; with potential as a therapeutic target in Alzheimer&rsquo;s disease.

No MeSH data available.


Related in: MedlinePlus