Increased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease.

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 beta-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.

Increased expression of the oligopeptidase THOP1 is a neuroprotective response to Abeta toxicity.

In a comprehensive proteomics study aiming at the identification of proteins associated with amyloid-beta (Abeta)-mediated toxicity in cultured cortical neurons, we have identified Thimet oligopeptidase (THOP1). Functional modulation of THOP1 levels in primary cortical neurons demonstrated that its overexpression was neuroprotective against Abeta toxicity, while RNAi knockdown made neurons more vulnerable to amyloid peptide. In the TgCRND8 transgenic mouse model of amyloid plaque deposition, an age-dependent increase of THOP1 expression was found in brain tissue, where it co-localized with Abeta plaques. In accordance with these findings, THOP1 expression was significantly increased in human AD brain tissue as compared to non-demented controls. These results provide compelling evidence for a neuroprotective role of THOP1 against toxic effects of Abeta in the early stages of AD pathology, and suggest that the observed increase in THOP1 expression might be part of a compensatory defense mechanism of the brain against an increased Abeta load.

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 ß-amyloid (Aß) 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-3ß 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 Aß deposition and pathology increases. CONCLUSIONS: Lithium, when given on time, stimulates neurogenesis and counteracts AD-like pathology.

Clioquinol decreases amyloid-beta burden and reduces working memory impairment in a transgenic mouse model of Alzheimer's disease.

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.

Combined treatment with atorvastatin and minocycline suppresses severity of EAE.

Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the central nervous system (CNS). An approach to improve MS treatment is to identify a rational combination of new medications or existing therapies that impact different aspects of the disease process. Statins are effective in the treatment of MS animal models and are promising candidates for future treatment. Minocycline ameliorates clinical severity of experimental autoimmune encephalomyelitis (EAE) and exhibits several anti-inflammatory and neuroprotective activities. In this study, we tested whether the combination of these two drugs could produce beneficial effects in EAE mice immunized with myelin oligodendrocyte protein (MOG). Our findings show that combined treatment, compared to using the medications alone, resulted in a significant reduction in disease severity, in both the acute and chronic phases of the disease, along with attenuation of inflammation, demyelination and axonal loss. Stereological analysis revealed that the combined treatment significantly guarded against neuroinflammation and neurodegeneration. Moreover, a significant suppression of anti-MOG antibody production in animals treated with the two medications was found. In conclusion, our findings prove that this combination of drugs is neuroprotective and suppresses the severity of EAE. Furthermore, this pharmacological approach appears to be promising as a future therapeutic strategy to control MS.

Abnormal processing of tau in the brain of aged TgCRND8 mice.

Amyloid plaques and neurofibrillary tangles are the main histopathological hallmarks of Alzheimer's disease (AD). In the neocortex and hippocampus of aged TgCRND8 mice, tau is hyperphosphorylated at different sites recognized by PHF-1, AT100, AT8 and CP13 antibodies. Phospho-SAPK/JNK levels were increased in the tg mouse brain, where activated SAPK/JNK co-localizes with PHF-1-positive cells. Phosphorylated tau-positive cells showed Bielschowsky- and Thioflavine S-positive intraneuronal deposits. PHF-1 and nitrotyrosine immunoreactivity merged within neurons surrounding amyloid deposits in cortical and hippocampal areas and immunoprecipitation studies confirmed that tau is nitrosylated. Our findings, demonstrating the presence of hyperphosphorylated and nitrosylated tau protein as well as of insoluble aggregates after the onset of amyloid deposition in the TgCRND8 mouse brain, indicate that the abnormal processing of tau may occur subsequently to cerebral amyloidosis and that activation of SAPK/JNK and induction of nitrosative stress are the more likely connecting factors between amyloidosis and tauopathy in AD.