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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.

No MeSH data available.


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Reduced CYFIP2 expression impairs the maintenance of spatial memory. (A) The experimental design for the hidden-platform training in the Morris water maze. Mice were trained with four trials per day for 10 days. Probe trials were given at the end of training Days 10 (P1) and 5 after the end of training (P2). (B) The time to reach the hidden platform did not differ between wild-type (n = 9) and Cyfip2+/− mutant mice (n = 7). Both groups improved with training. (C) Both wild-type and Cyfip2+/− mutants searched selectively target quadrant in a probe trial given immediately after training Day 10 (P1). However, Cyfip2+/− mutants did not search selectively in the second probe trial after 5 days of training (P2), in contrast to wild-type mice. Thus, the mutants cannot maintain spatial memory. TQ = target quadrant; OP = opposite quadrant; AL = adjacent left quadrant; AR = adjacent right quadrant. Means ± SEM; ***P < 0.001, **P < 0.01.
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aww205-F6: Reduced CYFIP2 expression impairs the maintenance of spatial memory. (A) The experimental design for the hidden-platform training in the Morris water maze. Mice were trained with four trials per day for 10 days. Probe trials were given at the end of training Days 10 (P1) and 5 after the end of training (P2). (B) The time to reach the hidden platform did not differ between wild-type (n = 9) and Cyfip2+/− mutant mice (n = 7). Both groups improved with training. (C) Both wild-type and Cyfip2+/− mutants searched selectively target quadrant in a probe trial given immediately after training Day 10 (P1). However, Cyfip2+/− mutants did not search selectively in the second probe trial after 5 days of training (P2), in contrast to wild-type mice. Thus, the mutants cannot maintain spatial memory. TQ = target quadrant; OP = opposite quadrant; AL = adjacent left quadrant; AR = adjacent right quadrant. Means ± SEM; ***P < 0.001, **P < 0.01.

Mentions: Hippocampus-dependent spatial memory is affected in the early stages of Alzheimer’s disease. To investigate whether reduced CYFIP2 expression affects spatial memory formation, we studied the Cyfip2+/− mutants and wild-type littermates in the hidden platform version of the water maze (Fig. 6). The mice were trained with four trials per day for 10 days. The genotypes did not differ in latency to locate the platform [two-way ANOVA with repeated measures; effect of genotype F(1,14) = 0.29, P = 0.60; effect of training F(9,126) = 18.9, P < 0.001; genotype × training interaction F(9,126) = 0.91, P = 0.52] (Fig. 6B). Studies with a separate cohort of mice indicated that Cyfip2+/− mutants had normal visible platform learning (time to reach platform for wild-type mice, 9.6 ± 1.5 s; for mutants, 11.1 ± 2.7 s; one-way ANOVA on ranks H = 0.025, P = 0.88. This indicates that the Cyfip2+/− mutants were not impaired in swimming abilities, motivation, and vision. To assess hippocampus-dependent spatial memory, probe trials were performed. A probe trial given at the end of training Day 10 (P1) showed that Cyfip2+/− mutants formed normal spatial memory after training (Fig. 6C). However, a second probe trial given 5 days after first probe test (P2) revealed that Cyfip2+/− mutants were impaired in retention of spatial memory, in contrast with wild-type littermates (Fig. 6C). During these probe trials the average swimming speed did not significantly differ between genotypes [P1: wild-type mice, 21.7 ± 2.0 cm/s; mutants, 24.3 ± 2.7 cm/s; one-way ANOVA with genotype as variable, F(1,14) = 4.58, P = 0.051; P2: wild-type, 22.1 ± 1.60 cm/s; mutants, 24.1 ± 2.3 cm/s; one-way ANOVA with genotype as variable, F(1,14) = 3.90, P = 0.068]. Analysis of search time in the four quadrants during probe trial P1 showed that Cyfip2+/− mutants and wild-type littermates searched selectively [one-way ANOVA with analysis of the quadrant as variable; mutants, F(3,24) = 9.65, P < 0.001; wild-type mice, F(3,32) = 17.3, P < 0.001] (Fig. 6C). The mutants and wild-type mice spent more time searching in the target quadrant than in any other quadrant (Student-Newman-Keuls test; mutants, P < 0.001 target quadrant versus opposite quadrant and adjacent left quadrant, P = 0.002 target quadrant versus adjacent right quadrant; wild-type, P < 0.001 target quadrant versus opposite quadrant, adjacent left quadrant, adjacent right quadrant). On the other hand, during probe trial P2 the Cyfip2+/− mutants searched randomly, spending similar times in all quadrants [one-way ANOVA with quadrant as variable, F(3,24) = 2.55, P = 0.08], in contrast with wild-type littermates [one-way ANOVA with quadrant as variable, F(3,32) = 8.47, P < 0.001]. The wild-type mice spent more time searching in the target quadrant than in any other quadrant (Student-Newman-Keuls test; P < 0.001 target quadrant versus opposite quadrant, P = 0.002 target quadrant versus adjacent right quadrant, P = 0.004 target quadrant versus adjacent left quadrant). Taken together, these results indicate that Cyfip2+/− mutants are able to form spatial memories, but they cannot maintain these memories.Figure 6


Alzheimer-related decrease in CYFIP2 links amyloid production to tau hyperphosphorylation and memory loss
Reduced CYFIP2 expression impairs the maintenance of spatial memory. (A) The experimental design for the hidden-platform training in the Morris water maze. Mice were trained with four trials per day for 10 days. Probe trials were given at the end of training Days 10 (P1) and 5 after the end of training (P2). (B) The time to reach the hidden platform did not differ between wild-type (n = 9) and Cyfip2+/− mutant mice (n = 7). Both groups improved with training. (C) Both wild-type and Cyfip2+/− mutants searched selectively target quadrant in a probe trial given immediately after training Day 10 (P1). However, Cyfip2+/− mutants did not search selectively in the second probe trial after 5 days of training (P2), in contrast to wild-type mice. Thus, the mutants cannot maintain spatial memory. TQ = target quadrant; OP = opposite quadrant; AL = adjacent left quadrant; AR = adjacent right quadrant. Means ± SEM; ***P < 0.001, **P < 0.01.
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aww205-F6: Reduced CYFIP2 expression impairs the maintenance of spatial memory. (A) The experimental design for the hidden-platform training in the Morris water maze. Mice were trained with four trials per day for 10 days. Probe trials were given at the end of training Days 10 (P1) and 5 after the end of training (P2). (B) The time to reach the hidden platform did not differ between wild-type (n = 9) and Cyfip2+/− mutant mice (n = 7). Both groups improved with training. (C) Both wild-type and Cyfip2+/− mutants searched selectively target quadrant in a probe trial given immediately after training Day 10 (P1). However, Cyfip2+/− mutants did not search selectively in the second probe trial after 5 days of training (P2), in contrast to wild-type mice. Thus, the mutants cannot maintain spatial memory. TQ = target quadrant; OP = opposite quadrant; AL = adjacent left quadrant; AR = adjacent right quadrant. Means ± SEM; ***P < 0.001, **P < 0.01.
Mentions: Hippocampus-dependent spatial memory is affected in the early stages of Alzheimer’s disease. To investigate whether reduced CYFIP2 expression affects spatial memory formation, we studied the Cyfip2+/− mutants and wild-type littermates in the hidden platform version of the water maze (Fig. 6). The mice were trained with four trials per day for 10 days. The genotypes did not differ in latency to locate the platform [two-way ANOVA with repeated measures; effect of genotype F(1,14) = 0.29, P = 0.60; effect of training F(9,126) = 18.9, P < 0.001; genotype × training interaction F(9,126) = 0.91, P = 0.52] (Fig. 6B). Studies with a separate cohort of mice indicated that Cyfip2+/− mutants had normal visible platform learning (time to reach platform for wild-type mice, 9.6 ± 1.5 s; for mutants, 11.1 ± 2.7 s; one-way ANOVA on ranks H = 0.025, P = 0.88. This indicates that the Cyfip2+/− mutants were not impaired in swimming abilities, motivation, and vision. To assess hippocampus-dependent spatial memory, probe trials were performed. A probe trial given at the end of training Day 10 (P1) showed that Cyfip2+/− mutants formed normal spatial memory after training (Fig. 6C). However, a second probe trial given 5 days after first probe test (P2) revealed that Cyfip2+/− mutants were impaired in retention of spatial memory, in contrast with wild-type littermates (Fig. 6C). During these probe trials the average swimming speed did not significantly differ between genotypes [P1: wild-type mice, 21.7 ± 2.0 cm/s; mutants, 24.3 ± 2.7 cm/s; one-way ANOVA with genotype as variable, F(1,14) = 4.58, P = 0.051; P2: wild-type, 22.1 ± 1.60 cm/s; mutants, 24.1 ± 2.3 cm/s; one-way ANOVA with genotype as variable, F(1,14) = 3.90, P = 0.068]. Analysis of search time in the four quadrants during probe trial P1 showed that Cyfip2+/− mutants and wild-type littermates searched selectively [one-way ANOVA with analysis of the quadrant as variable; mutants, F(3,24) = 9.65, P < 0.001; wild-type mice, F(3,32) = 17.3, P < 0.001] (Fig. 6C). The mutants and wild-type mice spent more time searching in the target quadrant than in any other quadrant (Student-Newman-Keuls test; mutants, P < 0.001 target quadrant versus opposite quadrant and adjacent left quadrant, P = 0.002 target quadrant versus adjacent right quadrant; wild-type, P < 0.001 target quadrant versus opposite quadrant, adjacent left quadrant, adjacent right quadrant). On the other hand, during probe trial P2 the Cyfip2+/− mutants searched randomly, spending similar times in all quadrants [one-way ANOVA with quadrant as variable, F(3,24) = 2.55, P = 0.08], in contrast with wild-type littermates [one-way ANOVA with quadrant as variable, F(3,32) = 8.47, P < 0.001]. The wild-type mice spent more time searching in the target quadrant than in any other quadrant (Student-Newman-Keuls test; P < 0.001 target quadrant versus opposite quadrant, P = 0.002 target quadrant versus adjacent right quadrant, P = 0.004 target quadrant versus adjacent left quadrant). Taken together, these results indicate that Cyfip2+/− mutants are able to form spatial memories, but they cannot maintain these memories.Figure 6

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