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In wild-type rats, lithium has been shown to reduce tau phosphorylation and inhibit GSK-3 activity [ ] and to also enhance spatial memory .
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Less clear, however, is the efficacy of lithium against tau-mediated degeneration. Mice that overexpress disease-linked tau exhibit reduced tau phosphorylation with lithium treatment [ 5573 — 75].
Lei 6938 81 em addition, tau transgenic models have attenuated axonal degeneration with lithium treatment [ 55 ], but no motor lei 6938 81 em working memory recovery [ ]. However, in accordance with cell culture studies [ 53— ] GSK-3 activity remained the same in a long-term 5 months lithium trial [ 74 ], possibly suggesting that the protection offered by lithium is GSK-3 independent.
The authors [ 74 ] alternatively suggested that lithium reduced the tau lesion primarily by promoting its ubiquitination and degradation rather than by inhibiting its phosphorylation through GSK Despite this, lithium has recently been evaluated as a therapy for AD in a week multicenter, randomized, single-blind, and placebo-controlled trial [ ].
The study concluded that lithium was not an effective therapeutic for AD, as there were no significant effects on any of the endpoint measurements.
A post-hoc examination on a subset of individuals did, however, reveal an increase in serum BDNF that was inversely correlated with decreased ADAS-Cog sum scores [ ]. lei 6938 81 em
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Further long-term studies are required to determine the safety and efficiency of lithium or other GSK-3 inhibitors for the treatment of AD. The data, however, are not conclusive, with lithium shown to both protect against the dopamine depletion resulting from MPTP toxicity [ ] and to also cause a decrease lei 6938 81 em brain dopamine DA release [ ] that leads to deficits in DA levels [ ].
There is, therefore, currently little evidence to support lei 6938 81 em as a treatment strategy for PD. The data on the use lei 6938 81 em lithium in other human neurodegenerative diseases is also not compelling. Lithium, for example, has also been investigated as a therapy for one of the motor-neuron diseases, amyotrophic lateral sclerosis ALSdespite the lack of an established connection with GSK Although lithium was found to delay disease onset and to reduce neurological deficits in both ALS mouse models and a small human trial , other mouse and human trials have shown detrimental effects .
The potential utility of lithium in ALS, or indeed in any of the neurodegenerative disorders outlined above, remains unclear.
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It is likely that lei 6938 81 em has other activities, independent of GSK-3, that may mediate its pharmacodynamics. Although extensive research has been undertaken in the last decade, the role of GSK-3 in disease pathogenesis has yet to be fully elucidated.
The intriguing preclinical data, however, has yet to be translated into an effective pharmacotherapy for neurodegeneration, perhaps in part owing to the complex regulation lei 6938 81 em GSK and its activity on multiple substrates. Future endeavors should investigate alternative modulators of GSK-3 and annotate more precise mechanisms of how the isoforms of GSK-3 participate in neurodegeneration.
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The authors thank Y. Hung for helpful discussions and proofreading.
Montejo De Garcini, and J. A property common to most cyclin-dependent kinase inhibitors?
International Journal of Alzheimer’s Disease
Further observations show a correlate of protection mediated by neutralizing antibodies NAbs 3 These findings are encouraging and indicate the lei 6938 81 em for vaccine-induced protective immunity in humans.
This residue fragment alone exhibited potent antiviral activity through blocking S-protein-mediated infection.
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Since this antibody also blocked the interaction lei 6938 81 em ACE2 and S glycoprotein, the ACE2-binding site of the S glycoprotein has become an attractive target for vaccine design We and others previously demonstrated that the receptor binding domain of the S protein contains a major neutralization determinant 61516which can induce potent NAbs that block SARS-CoV replication in monkeys 6.
Regardless lei 6938 81 em the forms of vaccines tested e. However, specific mapping of the major neutralizing epitope is yet to be determined.