A microRNA-signature that correlates with cognition and is a target against cognitive decline (2021)
Figure 6

Fig 6. Targeting the 3-microRNA signature reinstates cognitive function in mouse models for dementia.

A. Experimental design. Inhibitor mixture for 3-microRNAs (anti-miR mix) namely miR-181a-5p, miR-148-3p and miR-146a-5p was injected into the hippocampal CA of male wild type mice prior to behavioral testing. As control, scramble siRNAs were injected as described above. Experiments were performed in two mouse models representing Aging and Alzheimer´s disease (AD).

B. Escape latency during the water maze training comparing 3-month old (young-control, n = 18) mice and 16,5-month old (old-control, n = 18) injected with scramble control oligonucleotides and 16,5-month old mice injected with microRNA inhibitors (old miR-inhibtor mix, n = 20). Bars and error bars indicate mean ± sem.

C. Escape latency on final day of water maze training was impaired improved in old mice treated with the microRNA inhibitors mix. young-control (n = 18, 19.3 ± 15.23, mean ± std. deviation); old-control (n = 18, 36.31 ± 15.38, mean ± std. deviation); old-inhibitor (n = 20, 22.78 ± 13.85, mean ± std. deviation).

D. Depiction of the search strategies during the water maze training.

E. The cumulative cognitive score calculated for each day on the basis of hippocampal dependent strategies was significantly impaired when comparing mice old control mice to young control mice. Data is normalized to young control group. Bars and error bars indicate mean ± sem. Number of mice: young-control, n = 18; old-control, n = 18; old miR-inhibitor mix, n = 20.

F. Number of visits to the platform during the probe test. young-control (5.2 ± 2.5, mean ± std. deviation); old-control (2.7 ± 1.83, mean ± std. deviation); old-inhibitor (5.0 ± 2.3, mean ± std. deviation). All mice were male. Number of mice: young-control, n = 18; old-control, n = 18; old miR-inhibitor mix, n = 20.

G. Eigen value showing the expression of the 3-microRNA signature in the hippocampus of 4 and 8 months old APPPS1-21 mice. The center line indicates the median, while the upper and lower lines represent the 75th and 25th percentiles, respectively. The whiskers represent the smallest and largest values in the 1.5× interquartile range. Number of mice: 5-6/group.

H. Escape latency during the water maze training comparing 7 months old wild type mice (WT-control, n = 17, male: 9, female: 8) and APPPS-21 mice (APP-control, n = 8, male: 6, female: 2) injected with scramble control oligonucleotides and APPPS1-21 mice injected with microRNA inhibitors (APP miR-inhibtor mix, n = 12, male: 8, female: 4). Bars and error bars indicate mean ± sem..

I. Escape latency measured on the last day of water maze training was reduced in APP-control mice. However, learning performance was rescued in APP miR-inhibtor mix mice. WT-control: 20.43 ± 10.33 (mean ± std. deviation), APP-control: 40.92 ± 17.33 (mean ± std. deviation), APP miR-inhibitor mix: 22.04 ± 9.96 (mean ± std. deviation). Sex did not affect the data. Number of mice: WT-control, n = 17, male: 9, female: 8; APP-control, n = 8, male: 6, female: 2; APP miR-inhibtor mix, n = 12, male: 8, female: 4.

J. Depiction of the search strategies during the water maze training in experimental groups.

K. The cumulative cognitive score calculated for each day on the basis of hippocampal dependent strategies was significantly impaired when comparing WT control mice to APP control mice. Data is normalized to WT control group. Bars and error bars indicate mean ± sem. Number of mice: WT-control, n = 17, male: 9, female: 8; APP-control, n = 8, male: 6, female: 2; APP miR-inhibtor mix, n = 12, male: 8, female: 4.

L. Comparison of the number of visits to the platform during probe test. WT-control: 4.76 ± 1.82 (mean ± std. deviation), APP-control: 2.5 ± 2.5 (mean ± std. deviation), APP miR-inhibitor mix: 3.41 ± 2.15 (mean ± std. deviation). Bars and error bars indicate mean ± sem. Number of mice: WT-control, n = 17, male: 9, female: 8; APP-control, n = 8, male: 6, female: 2; APP miR-inhibtor mix, n = 12, male: 8, female: 4.

Data information: (B, H) Mixed-effects analysis followed by Tukey's multiple comparison test. (C, E, F, I, K, L) One-way ANOVA followed by Dunnett´s multiple comparisons test. (G) unpaired t-tests, two tailed. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.