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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 BACE1 expression at protein, but not mRNA level, and abnormal amyloid-β42 production in the hippocampus. (A) Representative western blots. (B) Quantification showed that BACE1 protein expression is significantly upregulated by ∼40% 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 Bace1 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) An ELISA on whole hippocampi showed significantly elevated amyloid-β42 levels by 30% in Cyfip2+/− mutants (black bar; n = 4) versus wild-type littermates (grey bar; n = 5). Means ± SEM are shown. *P < 0.05, **P < 0.01.
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aww205-F3: Reduced CYFIP2 expression leads to increased BACE1 expression at protein, but not mRNA level, and abnormal amyloid-β42 production in the hippocampus. (A) Representative western blots. (B) Quantification showed that BACE1 protein expression is significantly upregulated by ∼40% 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 Bace1 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) An ELISA on whole hippocampi showed significantly elevated amyloid-β42 levels by 30% in Cyfip2+/− mutants (black bar; n = 4) versus wild-type littermates (grey bar; n = 5). Means ± SEM are shown. *P < 0.05, **P < 0.01.

Mentions: Translation of the mRNA encoding β-site APP cleaving enzyme 1 (BACE1) is increased by amyloid-β42 action on cultured neurons (Sadleir et al., 2014; Mamada et al., 2015) and in an Alzheimer’s disease mouse model (Caccamo et al., 2015). As the elevated APP protein, but not mRNA, expression in Cyfip2+/− mutants (Fig. 2C–E) suggested that reduced CYFIP2 expression leads to increased translation of particular mRNAs, we tested whether BACE1 expression was altered. Western blot analysis showed that BACE1 protein expression was significantly elevated in hippocampal synaptosomes by ∼40% in Cyfip2+/− mice in comparison to wild-type littermates (t = 2.36, P < 0.05; Fig. 3A and B). This change was not observed in total hippocampal lysates (Supplementary Fig. 7A and B), possibly due to high levels of BACE1 expression in non-synaptic fractions (data not shown), suggesting BACE1 expression is mainly elevated at synapses in Cyfip2+/− mutants. Quantitative PCR analysis showed that the Bace1 mRNA expression level was not altered in the hippocampus of Cyfip2+/− mutants (t = 0.48, P = 0.64; Fig. 3C). Thus, reduced CYFIP2 expression impacts on the post-transcriptional expression of BACE1. In previous studies higher levels of BACE1 protein expression have been associated with abnormal APP cleavage and higher amyloid-β42 production (Caccamo et al., 2015). Therefore, we studied whether amyloid-β42 production is elevated in hippocampus of Cyfip2+/− mutants. As expected, an ELISA showed that amyloid-β42 production was increased by ∼30% in hippocampus of Cyfip2+/− mutants in comparison to wild-type littermates (t = 3.18, P < 0.01; Fig. 3D). These findings indicate that reduced CYFIP2 expression affects APP processing.Figure 3


Alzheimer-related decrease in CYFIP2 links amyloid production to tau hyperphosphorylation and memory loss
Reduced CYFIP2 expression leads to increased BACE1 expression at protein, but not mRNA level, and abnormal amyloid-β42 production in the hippocampus. (A) Representative western blots. (B) Quantification showed that BACE1 protein expression is significantly upregulated by ∼40% 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 Bace1 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) An ELISA on whole hippocampi showed significantly elevated amyloid-β42 levels by 30% in Cyfip2+/− mutants (black bar; n = 4) versus wild-type littermates (grey bar; n = 5). Means ± SEM are shown. *P < 0.05, **P < 0.01.
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aww205-F3: Reduced CYFIP2 expression leads to increased BACE1 expression at protein, but not mRNA level, and abnormal amyloid-β42 production in the hippocampus. (A) Representative western blots. (B) Quantification showed that BACE1 protein expression is significantly upregulated by ∼40% 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 Bace1 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) An ELISA on whole hippocampi showed significantly elevated amyloid-β42 levels by 30% in Cyfip2+/− mutants (black bar; n = 4) versus wild-type littermates (grey bar; n = 5). Means ± SEM are shown. *P < 0.05, **P < 0.01.
Mentions: Translation of the mRNA encoding β-site APP cleaving enzyme 1 (BACE1) is increased by amyloid-β42 action on cultured neurons (Sadleir et al., 2014; Mamada et al., 2015) and in an Alzheimer’s disease mouse model (Caccamo et al., 2015). As the elevated APP protein, but not mRNA, expression in Cyfip2+/− mutants (Fig. 2C–E) suggested that reduced CYFIP2 expression leads to increased translation of particular mRNAs, we tested whether BACE1 expression was altered. Western blot analysis showed that BACE1 protein expression was significantly elevated in hippocampal synaptosomes by ∼40% in Cyfip2+/− mice in comparison to wild-type littermates (t = 2.36, P < 0.05; Fig. 3A and B). This change was not observed in total hippocampal lysates (Supplementary Fig. 7A and B), possibly due to high levels of BACE1 expression in non-synaptic fractions (data not shown), suggesting BACE1 expression is mainly elevated at synapses in Cyfip2+/− mutants. Quantitative PCR analysis showed that the Bace1 mRNA expression level was not altered in the hippocampus of Cyfip2+/− mutants (t = 0.48, P = 0.64; Fig. 3C). Thus, reduced CYFIP2 expression impacts on the post-transcriptional expression of BACE1. In previous studies higher levels of BACE1 protein expression have been associated with abnormal APP cleavage and higher amyloid-β42 production (Caccamo et al., 2015). Therefore, we studied whether amyloid-β42 production is elevated in hippocampus of Cyfip2+/− mutants. As expected, an ELISA showed that amyloid-β42 production was increased by ∼30% in hippocampus of Cyfip2+/− mutants in comparison to wild-type littermates (t = 3.18, P < 0.01; Fig. 3D). These findings indicate that reduced CYFIP2 expression affects APP processing.Figure 3

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