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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 altered spine morphology in apical dendrites of CA1 pyramidal neurons. (A) Spines were classified as long-thin, filopodia, or stubby/mushroom, according to criteria set by Harris et al. (1992). Spines were imaged under bright-field microscopy using a 100× oil-immersion objective. Scale bar = 0.5 µm. (B) Spines classified as a proportion of total number of spines for apical dendritic segments of dorsal CA1 pyramidal neurons. Wild-type (WT) controls (black bars, n = 5) were compared to Cyfip2+/− mutants (grey bars, n = 4) for long-thin spines (39% versus 55%), filopodia (6.7% versus 7.5%), and stubby/mushroom (51% versus 36%). Cyfip2+/− mutants have significantly more long thin spines, but less stubby-mushroom spines than wild-type mice. (C) Spines classified as a proportion of total number of spines for basal dendritic segments of dorsal CA1 pyramidal neurons. Wild-type controls (black bars, n = 5) were compared to Cyfip2+/− mutants (grey bars, n = 4) for long-thin, filopodia, and stubby/mushroom spines. No difference was found between the genotypes. Means ± SEM are shown. *P < 0.05; **P < 0.01.
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aww205-F5: Reduced CYFIP2 expression leads to altered spine morphology in apical dendrites of CA1 pyramidal neurons. (A) Spines were classified as long-thin, filopodia, or stubby/mushroom, according to criteria set by Harris et al. (1992). Spines were imaged under bright-field microscopy using a 100× oil-immersion objective. Scale bar = 0.5 µm. (B) Spines classified as a proportion of total number of spines for apical dendritic segments of dorsal CA1 pyramidal neurons. Wild-type (WT) controls (black bars, n = 5) were compared to Cyfip2+/− mutants (grey bars, n = 4) for long-thin spines (39% versus 55%), filopodia (6.7% versus 7.5%), and stubby/mushroom (51% versus 36%). Cyfip2+/− mutants have significantly more long thin spines, but less stubby-mushroom spines than wild-type mice. (C) Spines classified as a proportion of total number of spines for basal dendritic segments of dorsal CA1 pyramidal neurons. Wild-type controls (black bars, n = 5) were compared to Cyfip2+/− mutants (grey bars, n = 4) for long-thin, filopodia, and stubby/mushroom spines. No difference was found between the genotypes. Means ± SEM are shown. *P < 0.05; **P < 0.01.

Mentions: CYFIP2 not only binds to FMRP, it is also part of the WAVE complex (Eden et al., 2002), which regulates actin polymerization. As CYFIP1 is also part of the WAVE complex and because reduced CYFIP1 expression affects dendritic spine morphology of hippocampal CA1 pyramidal neurons (De Rubeis et al., 2013; Pathania et al., 2014), we studied whether reduced CYFIP2 expression would also alter dendritic spines. Using Golgi-Cox staining, we analysed dendritic spines on apical and basal segments of CA1 pyramidal neurons of Cyfip2+/− mutants and wild-type littermates (Supplementary Fig. 8). There was no significant difference in spine density between the genotypes for apical distal segments (t = 0.095, P = 0.93) or for basal distal segments (t = 0.10, P = 0.92) (Supplementary Fig. 8C and D). Next, we categorized the spines into three classes: long-thin, filopodia and stubby-mushroom spines according to widely used criteria (Harris and Stevens, 1989; Harris et al., 1992) (Fig. 5A). Comparison of these spine types on apical distal dendrites revealed a significant difference between genotypes (Fig. 5B). Compared to wild-type littermates, Cyfip2+/− mutants had a greater proportion of long-thin spines (55% for mutants versus 39% for wild-types; t = 3.45, P < 0.05) and a smaller proportion of stubby/mushroom spines (36% for mutants versus 51% for wild-types; t = 3.51, P < 0.01). The proportion of filopodia, however, remained constant between the two groups (t = 0.61, P = 0.56). In contrast with the differences in apical spine morphology between genotypes, we found that the abundance of spine types on basal dendrites was not altered in Cyfip2+/− mutants (long-thin, t = 0.34, P = 0.75; filopodia, t = 0.99, P = 0.37; stubby/mushroom, t = 0.51, P = 0.63; Fig. 5C). These findings show that reduced CYFIP2 expression affects spine morphology only in particular dendritic segments of CA1 pyramidal neurons.Figure 5


Alzheimer-related decrease in CYFIP2 links amyloid production to tau hyperphosphorylation and memory loss
Reduced CYFIP2 expression leads to altered spine morphology in apical dendrites of CA1 pyramidal neurons. (A) Spines were classified as long-thin, filopodia, or stubby/mushroom, according to criteria set by Harris et al. (1992). Spines were imaged under bright-field microscopy using a 100× oil-immersion objective. Scale bar = 0.5 µm. (B) Spines classified as a proportion of total number of spines for apical dendritic segments of dorsal CA1 pyramidal neurons. Wild-type (WT) controls (black bars, n = 5) were compared to Cyfip2+/− mutants (grey bars, n = 4) for long-thin spines (39% versus 55%), filopodia (6.7% versus 7.5%), and stubby/mushroom (51% versus 36%). Cyfip2+/− mutants have significantly more long thin spines, but less stubby-mushroom spines than wild-type mice. (C) Spines classified as a proportion of total number of spines for basal dendritic segments of dorsal CA1 pyramidal neurons. Wild-type controls (black bars, n = 5) were compared to Cyfip2+/− mutants (grey bars, n = 4) for long-thin, filopodia, and stubby/mushroom spines. No difference was found between the genotypes. Means ± SEM are shown. *P < 0.05; **P < 0.01.
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aww205-F5: Reduced CYFIP2 expression leads to altered spine morphology in apical dendrites of CA1 pyramidal neurons. (A) Spines were classified as long-thin, filopodia, or stubby/mushroom, according to criteria set by Harris et al. (1992). Spines were imaged under bright-field microscopy using a 100× oil-immersion objective. Scale bar = 0.5 µm. (B) Spines classified as a proportion of total number of spines for apical dendritic segments of dorsal CA1 pyramidal neurons. Wild-type (WT) controls (black bars, n = 5) were compared to Cyfip2+/− mutants (grey bars, n = 4) for long-thin spines (39% versus 55%), filopodia (6.7% versus 7.5%), and stubby/mushroom (51% versus 36%). Cyfip2+/− mutants have significantly more long thin spines, but less stubby-mushroom spines than wild-type mice. (C) Spines classified as a proportion of total number of spines for basal dendritic segments of dorsal CA1 pyramidal neurons. Wild-type controls (black bars, n = 5) were compared to Cyfip2+/− mutants (grey bars, n = 4) for long-thin, filopodia, and stubby/mushroom spines. No difference was found between the genotypes. Means ± SEM are shown. *P < 0.05; **P < 0.01.
Mentions: CYFIP2 not only binds to FMRP, it is also part of the WAVE complex (Eden et al., 2002), which regulates actin polymerization. As CYFIP1 is also part of the WAVE complex and because reduced CYFIP1 expression affects dendritic spine morphology of hippocampal CA1 pyramidal neurons (De Rubeis et al., 2013; Pathania et al., 2014), we studied whether reduced CYFIP2 expression would also alter dendritic spines. Using Golgi-Cox staining, we analysed dendritic spines on apical and basal segments of CA1 pyramidal neurons of Cyfip2+/− mutants and wild-type littermates (Supplementary Fig. 8). There was no significant difference in spine density between the genotypes for apical distal segments (t = 0.095, P = 0.93) or for basal distal segments (t = 0.10, P = 0.92) (Supplementary Fig. 8C and D). Next, we categorized the spines into three classes: long-thin, filopodia and stubby-mushroom spines according to widely used criteria (Harris and Stevens, 1989; Harris et al., 1992) (Fig. 5A). Comparison of these spine types on apical distal dendrites revealed a significant difference between genotypes (Fig. 5B). Compared to wild-type littermates, Cyfip2+/− mutants had a greater proportion of long-thin spines (55% for mutants versus 39% for wild-types; t = 3.45, P < 0.05) and a smaller proportion of stubby/mushroom spines (36% for mutants versus 51% for wild-types; t = 3.51, P < 0.01). The proportion of filopodia, however, remained constant between the two groups (t = 0.61, P = 0.56). In contrast with the differences in apical spine morphology between genotypes, we found that the abundance of spine types on basal dendrites was not altered in Cyfip2+/− mutants (long-thin, t = 0.34, P = 0.75; filopodia, t = 0.99, P = 0.37; stubby/mushroom, t = 0.51, P = 0.63; Fig. 5C). These findings show that reduced CYFIP2 expression affects spine morphology only in particular dendritic segments of CA1 pyramidal neurons.Figure 5

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