Title

 

Authors

T. Ed Dami ¹, A. Fiorentini ¹, I. Luccarini ¹, C. Traini ¹, C. Grossi ¹ and F. Casamenti ¹.
 
¹Dept. of Pharmacology, School of Medicine, University of Florence, Italy

 

Abstract

Adult hippocampal neurogenesis plays an important role in learning and memory processes and its abnormal regulation might account for cognitive impairments associated with Alzheimer’s Disease (AD) (Li et al., 2008). Adult neurogenesis is positively regulated by Wnt signalling and growing evidence shows that lithium activates this pathway (Lie et al.  2005). In this study, the double TgCRND8 (Tg) mice of 2 and 7 months of age, resembling the early and advanced stages of Aß deposition, respectively, were used to examine in vivo the effect of lithium treatment on hippocampal neurogenesis and how it correlates with a reduced brain pathology and behavioural impairments. The Tg and wild-type (wt) mice of 2 and 7 months of age were intraperitoneally (i.p.) injected with 0.6 MLiCl (10 μl/g of body weight) or sterile NaCl (10 μl/g), once daily for 5 weeks. During the last three days of lithium treatment the mice were i.p. injected with BrdU (50 mg/kg of body weight, twice daily) and killed 24 h and 5 weeks after the last BrdU injection for the evaluation of cell proliferation and survival, respectively. BrdU labelling showed a significant decrease of cell proliferation in the subgranular zone (SGZ) of dentate gyrus of the hippocampus of saline-treated Tg compared to wt mice at the age of 3 months, (P<0.05).The decrease of hippocampal cell proliferation was associated with behavioural deficits in the Morris water maze and “step down” tasks and worsened with age and pathology severity. Five weeks after BrdU injection the survival, differentiation into neurons (DCX⁺) and maturation (NeuN⁺) of the proliferating cells were markedly reduced. Five weeks of lithium treatment to 2-month-old Tg mice markedly stimulated the proliferation and neuron fate specification of newborn cells, significantly reduced the amyloid-ß (Aβ) burden, and fully counteracted the transgene-induced impairments of cognitive functions. The drug stimulation of adult hippocampal neurogenesis was accompanied by a significant inactivation of GSK-3 and a concomitant increase in ß-catenin expression. 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 as brain Aβ deposition increases. In conclusion, this in vivo study demonstrates that lithium, when given on time, stimulates neurogenesis and provides neuroprotection against Aβ toxicity. In the cortex of 3-month-old Tg mice, 24 h after BrdU administration the majority of BrdU immunoreactivity was found within IBA1 positive microglial cells in the Aβ plaque surroundings.
This work was supported by MIUR (PRIN 2008) and Ente Cassa di Risparmio di Firenze (2010).
 
Li et al. (2008). J Neuropathol Exp Neurol 67:78-84.
Lie et al. (2005). Nature 437:1370-1375.