Table 3.
Results of animal studies testing the effect of lithium (a), rapamycin (b), rifampicin (c) and bosutinib (d) on cognition.
| Author, year | Cognitive tests | Outcomes | Significance | |
|---|---|---|---|---|
| a | Caccamo et al., 2007 | T-maze (Alternation %) | Wt Li−66.67 (8.7), ctrl−72.15 (2.4) | ± |
| Tg Li−55.71 (5.6), ctrl−55.21 (5.8) | ± | |||
| a | Nocjar et al., 2007 | Hole-board spatial discrimination task: | ||
| Search time (s) session 6 | Li−6 (1), Ctrl−20 (3) | + | ||
| Repeat visits (# lower = better) | Li−0.6 (0.1), Ctrl−1.5 (0.4) | + | ||
| Number of errors (# lower = better) | Li−1.6 (0.2), Ctrl−1.9 (0.2) | ± | ||
| T-maze delayed alternation task: | ||||
| Sessions to reach criterion (#) | Li−13.5 (1), Ctrl−20 (1.5) | + | ||
| Social conditioned place preference: | ||||
| Percent correct (%) | 1min Li−75 (2.5), Ctrl−72.5 (5) | ± | ||
| 3min Li−70 (3), Ctrl−58 (4) | + | |||
| 5min Li−65 (2.5), Ctrl−60 (2.5) | ± | |||
| Run time (min) | 1min Li−3.7 (1), Ctrl−1.9 (0.2) | NR | ||
| 3min Li−2.7 (0.5), Ctrl−2.8 (0.5) | ± | |||
| 5min Li−2.9 (0.5), Ctrl−3.2 (0.5) | ± | |||
| Preference for social chamber (s): | Li−280 (100), Ctrl−175 (100) | + | ||
| a | Rockenstein et al., 2007 | Morris water maze: | ||
| Meters to reach platform day 7 | Tg Li−3 (0.5), ctrl−11.5 (3) | + | ||
| Wt Li−3.25 (0.5), ctrl−3 (0.5) | ||||
| Platform crosses (#) | Tg Li−7 (1.5), ctrl−6 (1) | ± | ||
| Wt Li−6 (2), ctrl−7 (1) | ||||
| Time in target quadrant (s) | Tg Li−16 (3), ctrl−18 (2) | ± | ||
| Wt Li−15 (3), ctrl−16 (3) | ||||
| a | Fiorentini et al., 2010 | Morris water maze: | Early stage disease (3 months) | |
| Escape latency day 4 (s) | Li 35s (5s), ctrl 55s (2s) | +++ | ||
| Time in target section (%) | Li 7.4% (2.25%), ctrl 1.25% (1.25%) | ++ | ||
| Inhibitory avoidance test (s) | Li 27 (3), ctrl 9.5 (2) | +++ | ||
| Late stage disease (7 months) | ||||
| Escape latency day 4 (s) | Li 50 (2), ctrl 59 (1) | NR | ||
| Time in target section (%) | Li 1.5 (0.5), ctrl 1.5 (0.5) | ± | ||
| Inhibitory avoidance test | Li 14 (3.5), ctrl 8 (4) | ± | ||
| a | Toledo and Inestrosa, 2010 | Morris water maze: | ||
| Escape latency day 5 (s) | Tg Li−45 (9), ctrl−35 (7.5) | ± | ||
| WT ctrl−27 (10) | ||||
| Memory flexibility test: | ||||
| No. of trials to criterion (#) | Tg Li−7 (0.5), ctrl 12 (0.25) | + | ||
| WT ctrl−5 (0.25) | ||||
| a | Sy et al., 2011 | Morris water maze: | ||
| Escape latency during day 7 (s) | Li + Na−25 (2), ctrl + Na−17 (5) | NR | ||
| Li + LPS−26 (3), ctrl + LPS−20 (3) | NR | |||
| Probe trial (24 h) | ||||
| Time spent in target quadrant (s) | Li + Na−17.5 (4.5), ctrl + Na−22 (4) | ± | ||
| Li + LPS−19 (2), ctrl + LPS−13 (4) | ± | |||
| Latency to platform (s) | Li + Na−24 (6), ctrl + Na−17.5 (5) | ± | ||
| Li + LPS−26 (5), ctrl + LPS−47.5 (7.5) | + | |||
| Number of platform location crosses (#) | Li + Na−5 (1.3), ctrl + Na−5.4 (1) | ± | ||
| Li + LPS−3 (0.25), ctrl + LPS−1 (0.5) | + | |||
| a | Nunes et al., 2015 | Barnes maze: | Treated before deficits | |
| Escape latency (s; mean) | Li−40 (3), ctrl−75 (7) | + | ||
| Time in target quadrant (%) | Li−52.3 (6.8) Ctrl−22.8 (4.9) | +++ | ||
| Aversive memory test session (s) | Li−299 (298/300), Ctrl−216 (137/298) | ++ | ||
| Barnes maze: | Treated after deficits | |||
| Escape latency (s; mean) | Li – 25 (2), Ctrl – 75 (7) | + | ||
| Time in target quadrant (%) | Li−32 (4) Ctrl−22.8 (4.9) | ++ | ||
| Aversive memory test session (s): | Li−298 (139/298), Ctrl−216 (137/298) | + | ||
| a | Wilson et al., 2017 | Novel object recognition (preference ratio) | WT Li−0.39 (0.04), veh−0.43 (0.04) Tg AD Li−0.39 (0.02) veh−0.28 (0.02) | NR + |
| Morris water maze: | ||||
| Escape latency training day 5 (s) | WT Li−31 (7), veh−15 (5) | NR | ||
| Tg Li−40 (10) AD veh−33 (8) | ± | |||
| Time in target quadrant (%) | WT Li−44 (5), veh−48 (5) | ± | ||
| Tg AD Li−45 (3), veh−50 (8) | ± | |||
| Auditory fear conditioning task: | ||||
| Contextual (% freezing) | WT Li−60 (15), veh−79 (11) | ± | ||
| Tg AD Li−60 (10) veh−55 (10) | ± | |||
| Cued recall (% freezing) | WT Li−55 (15), veh−85 (10) | NR | ||
| Tg AD Li−63 (7), veh−30 (5) | + | |||
| a | Nery et al., 2014 | Avoidance behavior | ||
| % animals in non-stimulus area | Aβ inj Li 65 (2), ctrl: 55 (1) | +++ | ||
| a | McBride et al., 2010 | Treated before deficits | Alzheimer's Tg: | |
| Learning during training (%) | ||||
| psn[B3]/+ flies | Li 75(5) -> 45(10), ctrl 62.5(7.5) -> 51 (9) | +++ | ||
| psn[I2]/+ flies | Li 65(7.5) -> 30(10) ctrl 63(8) -> 52(8) | +++ | ||
| Short term memory (%) | ||||
| psn[B3]/+ flies | Li–Naive 90(2), trained 70(5) | ++ | ||
| Ctrl–Naive 76(6), trained 75(6) | ± | |||
| psn[I2]/+ flies | Li–Naive 88(2), trained 72(5) | + | ||
| Ctrl–Naive 83(5), trained 85 (3) | ± | |||
| Treated after deficits | ||||
| Learning during training (%) | ||||
| psn[B3]/+ flies | Li 65(7.5) -> 18(7), ctrl 70(5) -> 62.5(7.5) | +++ | ||
| psn[I2]/+ flies | Li 76(5) -> 18(7), ctrl 47.5(7.5) -> 35(7.5) | +++ | ||
| Short term memory (%) | ||||
| psn[B3]/+ flies | Li–Naive 90(4), trained 62.5(7.5) | ++ | ||
| Ctrl–Naive 70(8), trained 75(7) | ± | |||
| psn[I2]/+ flies | Li–Naive 84(6), trained 62.5(7.5) | ++ | ||
| Ctrl–Naive 57.5(7.5), trained 63(8) | ± | |||
| Treated before deficits | ||||
| Short term memory | Parkinson's Tg: | |||
| Li 80(4) -> 75(5), ctrl 82.5(5) -> 78(4) | ± | |||
| b | Spilman et al., 2010 | Morris water maze: | ||
| Escape latency day 4 (s) | Tg Rapa 32(3), ctrl 42(5) | + | ||
| WT Rapa 15(2.5), ctrl 32.5(3) | NR | |||
| Platform crosses (#) | Tg Rapa 2.5(0.5), ctrl 0.9(0.1) | +/± | ||
| WT Rapa 5(1), ctrl 3.1(0.4) | NR | |||
| b | Majumder et al., 2011 | Morris water maze: | ||
| Escape latency day 5 (s) | Pre-AD–Rapa 26.9(2.1), ctrl 37.96(2.9) | + | ||
| Est AD – Rapa 36(2), ctrl 37.96(2.9) | ± | |||
| YA–Rapa 20.7(1.05), ctrl 29.1(2.7) | + | |||
| MA–Rapa 32.5(1.5), ctrl 29.1(2.7) | ± | |||
| Trial time in target quadrant (s) | Pre-AD–Rapa 22.5(2.5), ctrl 15(2.5) | + | ||
| Est AD–Rapa 17.5(1.5), ctrl 15(2.5) | ± | |||
| YA–Rapa 29(2), ctrl 21.5(1.5) | + | |||
| MA–Rapa 21(1.5), ctrl 21.5(1.5) | ± | |||
| MWM platform crosses (#) | Pre-AD–Rapa 3.5(0.5), ctrl 1.95(0.25) | + | ||
| Est AD–Rapa 1.75(0.2), ctrl 1.95(0.25) | ± | |||
| YA–Rapa 5.25(0.3), ctrl 3.8 (0.25) | + | |||
| MA–Rapa 3.5 (0.2), ctrl 3.8 (0.25) | ± | |||
| Novel object recognition | Pre-AD–Rapa 65 (7), ctrl 50 (5) | + | ||
| Est AD–Rapa 55 (2.5), ctrl 50 (5) | ± | |||
| YA–Rapa 67.5(2.5), ctrl 70 (4) | ± | |||
| MA–Rapa 60 (5), ctrl 70 (4) | ± | |||
| b | Halloran et al., 2012 | Passive avoidance test (s) | MA–Rapa 200(40), ctrl 160(40) | ± |
| OA–Rapa 200(30), ctrl 100(20) | + | |||
| b | Majumder et al., 2012 | Morris water maze: | ||
| Escape latency day 5 (s) | YA–Rapa 21(1), ctrl 30(2.5) | + | ||
| MA–Rapa 31(2), ctrl 30(2.5) | ± | |||
| Time in target quadrant (s) | YA–Rapa 28.73(1.65), ctrl 21.3(1.24) | ++ | ||
| MA–Rapa 20.97(1.18), ctrl 21.3(1.24) | ± | |||
| Latency to platform (s) | YA–Rapa 20(2), ctrl 27(3) | + | ||
| MA–Rapa 31(3), ctrl 27(3) | ± | |||
| Platform crosses | YA–Rapa 5.3(0.2), ctrl 3.9(0.15) | +++ | ||
| MA–Rapa 3.5(0.25), ctrl 3.9 (0.15) | ± | |||
| b | Lin et al., 2013 | Morris water maze: | ||
| Escape latency day 5 training (s) | WT–rapa 28(4), ctrl 25(3) | |||
| AD–rapa 35(9), ctrl 40(4) | ± | |||
| Platform crosses (#) | WT rapa−3.1(0.5), ctrl 3.9(0.6) | |||
| AD rapa−2.1 (0.5), ctrl−0.75 (0.25) | + | |||
| b | Neff et al., 2013 | Object place recognition (s) | YA rapa–novel 22(3), known 12(2) | ± |
| YA veh–novel 24(4), known 14(2) | ||||
| MA rapa–novel 15(3), known 10(2) | ± | |||
| MA veh–novel 17(2), known 15(4) | ||||
| Morris water maze: | ||||
| Escape latency day 5 (s) | YA rapa 30(1), veh 41 (2) | +/± | ||
| MA rapa 37 (3), veh 39 (1) | +/± | |||
| Time in target quadrant (s) | YA rapa 25(2), veh 21 (2) | ++ | ||
| MA rapa 25 (2), veh 20 (3) | ++ | |||
| Target crossings (#) | YA rapa 2.3(0.2), veh 1.3(0.2) | ++ | ||
| MA rapa 1.5 (0.3), veh 1.5 (0.2) | ± | |||
| Context fear conditioning: | ||||
| Activity suppression (ratio) | YA rapa 0.2 (0.02), veh 0.21 (0.02) | ++ | ||
| MA rapa 0.195 (0.01), veh 0.28 (0.02) | ++ | |||
| OA rapa 0.195 (0.01), veh 0.25 (0.04) | ++ | |||
| b | Wang et al., 2014 | Morris water maze: | ||
| Escape latency day 4 (s) | Rapa 25(3), ctrl 35(4) | + | ||
| Escape latency trial (s) | Rapa 16(5), ctrl 32(2.5) | ++ | ||
| Time in target quadrant (s) | Rapa 26(3.5), ctrl 12.5(1) | ++ | ||
| b | Zhu et al., 2014 | Morris water maze: | ||
| Escape latency (s) | Scop + rapa−50 (7.5) | − | ||
| Scop + saline−38 (5) | ++ | |||
| Saline only−55 (7) | ||||
| Scop + rapa + MAD−39 (4) | + | |||
| Time in target quadrant (%) | Scop + rapa−65 (7) | − | ||
| Scop + saline−80 (8) | + | |||
| Saline only−62 (6) | ||||
| Scop + rapa + MAD−75 (7.5) | + | |||
| b | Lin et al., 2015 | Morris water maze: | ||
| Escape latency (s) | Rapa 25(1), ctrl 19(2) | ± | ||
| Platform crosses (#) | Rapa 1.6(0.25), ctrl 1.75(0.25) | ± | ||
| b | Wang et al., 2016 | Y-maze (alternation %): | ||
| 4wks post infusion | Rapa 39(6), ctrl 62(10) | − | ||
| 8 wks post infusion | Rapa 48(7), ctrl 53(8) | ± | ||
| b | Jahrling et al., 2017 | Morris water maze: | ||
| Escape latency day 4 (s) | Rapa 30(4), ctrl 40(5) | +++ | ||
| Trial time in target quadrant (%) | Rapa 32(6), ctrl 13(2) | + | ||
| Spatial Novelty (>0.33 = intact) | Rapa 0.44 (0.02), ctrl 0.34 (0.02) | +++ | ||
| b | Zhang et al., 2017 | Morris water maze: | ||
| Escape latency day 5 (s) | Rapa−32.5(5), veh 67(13) | +++ | ||
| Time in target quadrant (%) | Rapa−42.5(7.5), veh 22.5(7.5) | + | ||
| Number of platform crossings (#) | Rapa−3.75 (5.5), veh−1.5 (0.5) | + | ||
| c | Umeda et al., 2016 | Morris water maze: | ||
| Escape latency day 5 (s) | 12m APP rif−19(5), veh−35(6) | ++ | ||
| 18m APP veh−36(5) | ||||
| 18m APP rif0.5mg−29(5) | ± | |||
| 18m APP rif1mg−17.5(5) | ++ | |||
| 8m Tau609 rif0.5mg 14(2.3), veh−41(8) | + | |||
| 15m Tau609 rif1mg 29(7), veh 43(7) | ± | |||
| Time in target quadrant (%) | 12m APP rif−45(5), veh−29(3) | ± | ||
| 18m APP veh−29(6) | ||||
| 18m APP rif0.5mg−37(6) | ± | |||
| 18m APP rif1mg−49(4) | + | |||
| 8m Tau609 rif0.5mg 30(4), veh−16(7) | + | |||
| 15m Tau609 rif0.5mg 42(10), veh−21(9) | ± | |||
| d | Lonskaya et al., 2013 | Morris water maze: | ||
| Time in target quadrant (%) | Aβ icv bosu 29(1), ctrl 19 (1) | + | ||
| Time in target quadrant (% of WT) | Tg bosu 87.5(15) ctrl 75(10) | + | ||
| Platform crosses (#) | Aβ icv bosu 5.5 (0.5), ctrl 4 (0.25) | + | ||
| Platform crosses (% WT) | Tg bosu 147.5(7.5), ctrl 80(5) | + |
+++ favoring intervention, highly significant p < 0.001. ++ favoring intervention, significant p < 0.01. + favoring intervention, significant p < 0.05. +/± trend favoring intervention, p < 0.1. ± not significant. +/± trend favoring control, p < 0.1. –favoring control, significant p < 0.05. – favoring control, significant p < 0.01. — favoring control, highly significant p < 0.001. LPS, lipopolysaccharide; MA, treated from middle age; MAD, 3-methyladenine; NR, p-value not reported; OA, treated from old age; Scop, scopolamine; YA, treated from young adulthood.