Abstract
BackgroundAlzheimer'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.Methodology/Principal FindingsThe 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.ConclusionsLithium, when given on time, stimulates neurogenesis and counteracts AD-like pathology.
Highlights
In the adult Central Nervous System (CNS), neurogenesis occurs throughout the lifetime
Adult neurogenesis is a process by which new neurons are produced from neural stem cells (NSCs) and has consistently been found in two ‘‘neurogenic regions’’ of the brain in vivo: the subgranular zone (SGZ) of dentate gyrus (DG) in the hippocampus, which supplies new neurons for the dentate granular cell layer (GCL) and the subventricular zone (SVZ) lining the lateral ventricles in the forebrain, which supplies new interneurons for the olfactory bulb [1],[2]
Hippocampal neurogenesis appears to play an important role in learning and memory processes and mood regulation and its abnormal regulation might account for cognitive impairments associated with Alzheimer’s disease (AD) and may underlie neuropsychiatric disorders like major depression [5,6,7]
Summary
In the adult Central Nervous System (CNS), neurogenesis occurs throughout the lifetime. Adult NSCs have the ability to self-renew and to differentiate into neurons, astrocytes and oligodendrocytes in all mammalian CNS, including humans [3] In both SGZ and SVZ neurogenic regions, neurogenesis progress as a multi-step process which starts with the proliferation of NSCs. For the hippocampus, conceptually, this process has been divided into four steps: (i) proliferation of NSCs, (ii) neuronal fate determination of NSCs, (iii) survival and maturation of new neurons and (iv) functional integration of new neurons into the pre-existent neuronal network [4]. Hippocampal neurogenesis appears to play an important role in learning and memory processes and mood regulation and its abnormal regulation might account for cognitive impairments associated with Alzheimer’s disease (AD) and may underlie neuropsychiatric disorders like major depression [5,6,7].
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