Lithium Improves Hippocampal Neurogenesis, Neuropathology and Cognitive Functions in APP Mutant Mice

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive deterioration of cognitive functions, extracellular b-amyloid (Ab) plaques and intracellular neurofibrillary tangles within neocortex and hippocampus. Adult hippocampal neurogenesis plays an important role in learning and memory processes and its abnormal regulation might account for cognitive impairments associated with AD. Methodology/Principal Findings: The double transgenic (Tg) CRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein), aged 2 and 6 months, were used to examine in vivo the effects of 5 weeks lithium treatment. BrdU labelling showed a decreased neurogenesis in the subgranular zone of Tg mice compared to non-Tg mice. The decrease of hippocampal neurogenesis was accompanied by behavioural deficits and worsened with age and pathology severity. The differentiation into neurons and maturation of the proliferating cells were also markedly impaired in the Tg mice. Lithium treatment to 2-month-old Tg mice significantly stimulated the proliferation and neuron fate specification of newborn cells and fully counteracted the transgene-induced impairments of cognitive functions. The drug, by the inhibition of GSK-3b and subsequent activation of Wnt/ß-catenin signalling promoted hippocampal neurogenesis. Finally, the data show that the lithium’s ability to stimulate neurogenesis and cognitive functions was lost in the aged Tg mice, thus indicating that the lithium-induced facilitation of neurogenesis and cognitive functions declines a

“Step-down” inhibitory avoidance task in saline- and lithium-treated 3- and 7-month-old wild type and TgCRND8 mice.

<p>No statistically significant differences are present in the mean training latencies among groups. In the group of 3 months of age, one-way ANOVA plus Bonferroni's post comparison test shows a statistically significant increase in the mean retention latencies in saline- and lithium-treated wt and lithium-treated Tg mice, as compared to their respective training latencies, <i>*</i>P<0.001. Saline-treated Tg mice do not show significant differences between training and retention latencies (P>0.05). The retention latencies of saline-treated Tg mice significantly differ from the retention latencies of all the other groups (§P<0.001). In the group of 7 months of age, one-way ANOVA plus Bonferroni's post comparison test shows a statistically significant increase in the mean retention latencies in saline-and lithium-treated wt mice, as compared to their respective training latencies, <i>*</i>P<0.05. No significant differences are revealed between training and retention latencies in saline-and lithium- treated Tg mice (P>0.05). The retention latencies of saline-and lithium-treated Tg mice are significantly different from the retention latencies of all other groups (§P<0.05). Data are reported as mean ± S.E.M. White bars = training latencies, black bars = retention latencies, S = saline, L = lithium, Tg: TgCRND8, wt: wild type.</p

Effects of chronic lithium treatment on Morris water maze performances of wild type and TgCRND8 mice.

<p>A,B: training trials. Latencies to find the platform during the training session are reported as mean ± S.E.M. Each point represents the mean daily values of four trials per day. Statistics were performed using one-way ANOVA plus Bonferroni's post comparison test. In the group of 3 months of age, the saline- and lithium-treated wt mice show significantly shorter escape latencies with respect to saline-treated Tg mice over sessions (day 1: ^•P<0.05, days 2–4: *P<0.001). In lithium-treated Tg mice the recorded latencies are significantly higher than those of saline-treated Tg mice (day 2: °P<0.05; day 3: ^•P<0.05 and day 4: *P<0.001) and of saline- and lithium-treated wt mice (day 1: ^•P<0.05). In the group of 7 months of age, saline-and lithium-treated wt mice perform at significantly shorter latencies as compared to the Tg groups over sessions (***P<0.001 saline-treated wt vs saline-treated Tg; **P<0.01 saline- and lithium-treated wt vs lithium-treated Tg mice *P<0.05 lithium-treated wt vs lithium-treated Tg). C, D: bar graphs showing the percentage of time spent in the target section during the probe trial within 30 s. Data are reported as mean ± S.E.M. Statistics were performed using one-way ANOVA plus Bonferroni's post comparison test. In the group of 3 months of age, saline-treated Tg mice spend a significantly shorter percentage of time in the target section than saline- and lithium-treated wt mice (*P<0.01) and lithium-treated-Tg mice (^•P<0.05). In the group of 7 months of age, saline- and lithium-treated Tg mice are significantly impaired as compared to wt groups (*P<0.01). Top left is depicted the target section of the Morris water maze between red lines.</p