Results: 4

1.
Fig. 2.

Fig. 2. From: Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model.

STEP knockout restores synaptosomal membrane NR1/NR2B levels in 3xTg-AD mice. NMDAR levels were analyzed in hippocampal synaptosomal fractions (LP1) of WT, 3xTg-AD, STEP−/−, and DM mice. Representative immunoblots from 6-mo-old mice show pNR2B, NR2B, NR1, and NR2A. Histograms are shown in Lower panel. 3xTg-AD mice showed significantly lower levels of synaptosomal pNR2B Y1472, NR2B, and NR1 compared with WT (pNR2B Y1472, NR2B: *P < 0.05; NR1: **P < 0.01). No differences were found in NR2A levels (P > 0.05; n = 8). STEP−/− had significantly higher levels of synaptosomal pNR2B Y1472, NR2B, and NR1 compared with WT (*P < 0.05) but not NR2A (P > 0.05; n = 8). In DM mice, pNR2B Y1472, NR2B, and NR1 synaptosomal levels were increased compared with WT (*P < 0.05; n = 8) and 3xTg-AD mice (P < 0.05; n = 8) but were not significantly different from STEP−/− (P > 0.05; n = 8). Normalization was to GAPDH. STEP61 levels were significantly increased in 3xTg-AD brain membrane fractions compared with WT littermates (*P < 0.05; n = 4).

Yongfang Zhang, et al. Proc Natl Acad Sci U S A. 2010 November 2;107(44):19014-19019.
2.
Fig. 4.

Fig. 4. From: Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model.

Hippocampal synaptic plasticity is enhanced in 3xTg-AD mice lacking STEP. (A) Field potentials were recorded in the CA1 region of hippocampal slices from 10-mo-old 3xTg-AD mice with or without STEP. A stable baseline was recorded for at least 20 min before LTP induction by θ-burst stimulation (TBS). Inset shows traces before and after TBS. The slope of the EPSP relative to the pre-TBS level is plotted as a function of time. For 3xTg-AD, seven slices from three animals were used; for DM, six slices from three animals were used. Data are means ± SEM from separate slices. The increase in EPSP between 30 and 60 min post-TBS was greater in DM slices than 3xTg-AD slices (repeated measures ANOVA; P < 0.05). (B and C) Basal synaptic transmission and paired pulse response were indistinguishable between 3xTg-AD and DM mice.

Yongfang Zhang, et al. Proc Natl Acad Sci U S A. 2010 November 2;107(44):19014-19019.
3.
Fig. 3.

Fig. 3. From: Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model.

Absence of STEP in 3xTg-AD does not alter Aβ or tau levels. (A) 3xTg-AD and DM had no significant differences in total Aβ1–42 levels as measured by ELISA (P > 0.05; n = 4). (B) Immunoprecipitation from mouse brain homogenates used 6E10 antibody, and samples were also blotted with 6E10 antibody. CTFs and Aβ are indicated by arrowheads. Representative Aβ-enriched conditioned medium (7PA2-CM) immunoreactivity showing Aβ-monomer, dimer, and trimers (Right). 3xTg-AD and DM brain samples showed no significant difference in Aβ levels (P > 0.05). (C) In hippocampus, 3xTg-AD and DM 6-mo-old mice have similar patterns of intraneuronal and extracellular staining with 6E10. STEP−/− and WT mice showed no detectable staining with 6E10. (D) tau pathology was evaluated with an antibody that recognizes p-Ser235 and p-Thr231 (AT180) and (E) a human-specific tau antibody (HT7). 3xTg-AD or DM mice had no significant differences in immunoreactivity staining with either tau antibody. STEP−/− and WT mice showed no detectable staining with these antibodies. (Magnification: 10×; scale bar: 200 μm.) CA, cornu ammonis; Fi, fissure. (F) Quantification of 6E10 staining revealed no significant difference between 3xTg-AD and DM mice (one-way ANOVA with Fisher's LSD post hoc tests; P > 0.05). (G) Quantification of p-tau (AT180) and total tau (HT7) staining also revealed no significant differences between 3xTg-AD and DM mice (one-way ANOVA with Fisher's LSD post hoc tests; P > 0.05). (H) Mouse brain membrane fractions were probed with p-tau antibody and total tau antibody (P > 0.05; n = 4).

Yongfang Zhang, et al. Proc Natl Acad Sci U S A. 2010 November 2;107(44):19014-19019.
4.
Fig. 1.

Fig. 1. From: Genetic reduction of striatal-enriched tyrosine phosphatase (STEP) reverses cognitive and cellular deficits in an Alzheimer's disease mouse model.

Reduction of STEP levels improves cognitive function in 3xTg-AD mice. (A) In the hidden platform trials of the Morris water maze, 6-mo-old wild-type (WT; n = 11), STEP−/− (n = 9), and 3xTg-AD/STEP−/− [n = 17; double mutant (DM)] mice significantly outperformed 3xTg-AD mice (n = 25) in escape latencies [one-way (genotype) repeated measures (session) ANOVA with Fisher's least significant difference post hoc tests; **P < 0.002]. DM mice did not significantly differ from WT or STEP−/− mice (P > 0.05). (B) In probe trials performed 90 min after the final training trial on days 3, 6, and 9, WT, STEP−/−, and DM mice spent more time in the target quadrant than 3xTg-AD [one-way (genotype) repeated measures (day) ANOVA with Fisher's LSD post hoc tests; *P < 0.05]. The same effect was seen in a final probe trial 24 h after the last training trial (one-way ANOVA with Fisher's post hoc; *P < 0.05). (C) No significant differences were detected among groups in the visible platform trials [one-way (genotype) repeated measures (day) ANOVA with Fisher's LSD post hoc tests; P > 0.05]. (D) 3xTg-AD mice (n = 31) exhibited an impairment in spontaneous alternation in a Y maze compared with all other groups (one-way ANOVA with Fisher's post hoc; *P < 0.02). DM mice (n = 20) did not differ in spontaneous alternation compared with WT (n = 18) and STEP−/− (n = 18) mice (P > 0.05). (E) In an object recognition task, 3xTg-AD mice (n = 10) were outperformed by all other groups (one-way ANOVA with Fisher's post hoc tests; P < 0.05) and did not exhibit a preference for the novel object relative to chance (dashed line at 15 s; one-sample t test; P > 0.05). In contrast, WT (n = 10), STEP−/− (n = 8), and DM (n = 7) mice spent significantly more time than chance with the novel object (one-sample t test; *P < 0.02).

Yongfang Zhang, et al. Proc Natl Acad Sci U S A. 2010 November 2;107(44):19014-19019.

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