J. Neurochem. (2010) 112, 1539–1551. Abstract To investigate the role of the Wnt inhibitor Dickkopf‐1 (DKK‐1) in the pathophysiology of neurodegenerative diseases, we analysed DKK‐1 expression and localization in transgenic mouse models expressing familial Alzheimer’s disease mutations and a frontotemporal dementia mutation. A significant increase of DKK‐1 expression was found in the diseased brain areas of all transgenic lines, where it co‐localized with hyperphosphorylated tau‐bearing neurons. In TgCRND8 mice, DKK‐1 immunoreactivity was detected in neurons surrounding amyloid deposits and within the choline acetyltransferase‐positive neurons of the basal forebrain. Active glycogen synthase kinase‐3 (GSK‐3) was found to co‐localize with DKK‐1 and phospho‐tau staining. Downstream to GSK‐3, a significant reduction in β‐catenin translocation to the nucleus, indicative of impaired Wnt signaling functions, was found as well. Cumulatively, our findings indicate that DKK‐1 expression is associated with events that lead to neuronal death in neurodegenerative diseases and support a role for DKK‐1 as a key mediator of neurodegeneration with therapeutic potential.

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.

Clioquinol (CQ) is a "metal protein attenuating compound" that crosses the blood-brain barrier and binds, with high affinity, copper(II) and zinc(II), two metal ions critically involved in amyloid-beta aggregation and toxicity. CQ was recently proposed for the treatment of Alzheimer's disease, but controversial data have been reported so far concerning its real therapeutic advantages. We describe here results of chronic CQ treatment in the TgCRND8 mouse model of Alzheimer's disease. Remarkably, based on classical behavioral tests, CQ treatment was found to reverse, to a large extent, the working memory impairments that are characteristic of this mouse model. Pairwise, a significant reduction of amyloid-beta plaque burden, both in the cortex and in the hippocampus, was detected as well as an attenuation of astrogliosis. MALDI Mass Spectrometry Imaging technique revealed a specific localization of CQ in the above mentioned brain areas. Modest but significant effects on the absolute and relative brain concentrations of the three most important biometals (i.e., copper, zinc, and iron) were highlighted following CQ treatment. The pharmacological and mechanistic implications of the above findings are thoroughly discussed.

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