title: Lithium improves hippocampal neurogenesis, neuropathology and cognitive functions in APP mutant mice.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration of cognitive functions, extracellular β-amyloid (Aβ) 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.
  
  
  RESULTS
  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-3β 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 as brain Aβ deposition and pathology increases.
  
  
  CONCLUSIONS
  Lithium, when given on time, stimulates neurogenesis and counteracts AD-like pathology.
authors.affiliation: Department of Pharmacology, University of Florence, Florence, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Fiorentini
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Rosi
authors.forename: Cristina
authors.initials: C
authors.lastname: Grossi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Luccarini
authors.forename: Fiorella
authors.initials: F
authors.lastname: Casamenti
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002470:Cell Survival; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D018891:Dentate Gyrus / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D014150:Antipsychotic Agents; D051153:Wnt Proteins; D008094:Lithium