Microdose Lithium Treatment Stabilized Cognitive Impairment in Patients with Alzheimer’s Disease

Nunes, Marielza Andrade; Viel, Tânia Araújo; Buck, Hudson Sousa

doi:10.2174/1567205011310010014

Cited by 85 publications

(55 citation statements)

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“…8 Nunes and colleagues observed in a 18-month clinical study that AD patients treated daily with micro-doses of lithium performed at a consistent level on the mini-mental status exam, indicating arrested cognitive decline compared with the placebo-group. 9 Moreover, Forlenza and colleagues reported in their 1-year clinical trial study that patients with amnestic mild cognitive impairment treated with chronic low-dose lithium progressed less to AD compared with the placebo-group. 7 The treated patients performed higher on the cognition subscale of the AD Assessment Scale and had decreased concentrations of phosphorylated tau in their cerebrospinal fluid (CSF), indicating lithium as a potential therapeutic for AD.…”

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confidence: 99%

RETRACTED ARTICLE:LISPRO mitigates β-amyloid and associated pathologies in Alzheimer’s mice

Habib

Sawmiller

et al. 2017

Cell Death Dis

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Lithium has been marketed in the United States of America since the 1970s as a treatment for bipolar disorder. More recently, studies have shown that lithium can improve cognitive decline associated with Alzheimer’s disease (AD). However, the current United States Food and Drug Administration-approved lithium pharmaceutics (carbonate and citrate chemical forms) have a narrow therapeutic window and unstable pharmacokinetics that, without careful monitoring, can cause serious adverse effects. Here, we investigated the safety profile, pharmacokinetics, and therapeutic efficacy of LISPRO (ionic co-crystal of lithium salicylate and l-proline), lithium salicylate, and lithium carbonate (Li2CO3). We found that LISPRO (8-week oral treatment) reduces β-amyloid plaques and phosphorylation of tau by reducing neuroinflammation and inactivating glycogen synthase kinase 3β in transgenic Tg2576 mice. Specifically, cytokine profiles from the brain, plasma, and splenocytes suggested that 8-week oral treatment with LISPRO downregulates pro-inflammatory cytokines, upregulates anti-inflammatory cytokines, and suppresses renal cyclooxygenase 2 expression in transgenic Tg2576 mice. Pharmacokinetic studies indicated that LISPRO provides significantly higher brain lithium levels and more steady plasma lithium levels in both B6129SF2/J (2-week oral treatment) and transgenic Tg2576 (8-week oral treatment) mice compared with Li2CO3. Oral administration of LISPRO for 28 weeks significantly reduced β-amyloid plaques and tau-phosphorylation. In addition, LISPRO significantly elevated pre-synaptic (synaptophysin) and post-synaptic protein (post synaptic density protein 95) expression in brains from transgenic 3XTg-AD mice. Taken together, our data suggest that LISPRO may be a superior form of lithium with improved safety and efficacy as a potential new disease modifying drug for AD.

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confidence: 99%

RETRACTED ARTICLE:LISPRO mitigates β-amyloid and associated pathologies in Alzheimer’s mice

Habib

Sawmiller

et al. 2017

Cell Death Dis

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“…Encouraging findings for targeting GSK3 have been identified in examinations of dementia development in bipolar patients that have been treated with lithium for long periods of time, as these patients often have a lower prevalence of dementia than the general population (Nunes et al, 2007; Kessing et al, 2010). Clinical trials of lithium in Alzheimer’s disease have demonstrated some beneficial effects (Forlenza et al, 2012; Nunes et al, 2013), although not in all studies (Hampel et al, 2009). An initial trial of another GSK3 inhibitor, Tideglusib, did not demonstrate remarkable protective effects in Alzheimer’s disease patients, although it was designed as a safety trial, not as a therapeutic trial (del Ser et al, 2013).…”

Section: Targeting Gsk3 Therapeuticallymentioning

confidence: 99%

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Beurel

Grieco

Jope

2015

Pharmacology & Therapeutics

1,347

1,178

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Glycogen synthase kinase-3 (GSK3) may be the busiest kinase in most cells, with over 100 known substrates to deal with. How does GSK3 maintain control to selectively phosphorylate each substrate, and why was it evolutionarily favorable for GSK3 to assume such a large responsibility? GSK3 must be particularly adaptable for incorporating new substrates into its repertoire, and we discuss the distinct properties of GSK3 that may contribute to its capacity to fulfill its roles in multiple signaling pathways. The mechanisms regulating GSK3 (predominantly post-translational modifications, substrate priming, cellular trafficking, protein complexes) have been reviewed previously, so here we focus on newly identified complexities in these mechanisms, how each of these regulatory mechanism contributes to the ability of GSK3 to select which substrates to phosphorylate, and how these mechanisms may have contributed to its adaptability as new substrates evolved. The current understanding of the mechanisms regulating GSK3 is reviewed, as are emerging topics in the actions of GSK3, particularly its interactions with receptors and receptor-coupled signal transduction events, and differential actions and regulation of the two GSK3 isoforms, GSK3α and GSK3β. Another remarkable characteristic of GSK3 is its involvement in many prevalent disorders, including psychiatric and neurological diseases, inflammatory diseases, cancer, and others. We address the feasibility of targeting GSK3 therapeutically, and provide an update of its involvement in the etiology and treatment of several disorders.

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“…Normally, GSK3β is constitutively expressed in all cells and primarily inhibited via phosphorylation of serine-9 [198]. Lithium can increase GSK3β phosphorylation indirectly [199], thereby reducing its tau hyperphosphorylation activity and stabilising cognitive ability in AD patients [200]. Comparison of the ratio of Ser-9-phosphorylated GSK3β versus total GSK3β in platelets of AD patients and controls revealed a significant reduction in AD and MCI samples, indicating seriously enhanced enzyme activity [54].…”

Section: Reviewmentioning

confidence: 99%

Platelets, a reliable source for peripheral Alzheimer’s disease biomarkers?

Veitinger

Varga

Guterres

et al. 2014

acta neuropathol commun

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Peripheral biomarkers play an indispensable role in quick and reliable diagnoses of any kind of disease. With the population ageing, the number of people suffering from age-related diseases is expected to rise dramatically over the coming decades. In particular, all types of cognitive deficits, such as Alzheimer’s disease, will increase. Alzheimer’s disease is characterised mainly by coexistence of amyloid plaques and neurofibrillary tangles in brain. Reliable identification of such molecular characteristics antemortem, however, is problematic due to restricted availability of appropriate sample material and definitive diagnosis is only possible postmortem. Currently, the best molecular biomarkers available for antemortem diagnosis originate from cerebrospinal fluid. Though, this is not convenient for routine diagnosis because of the required invasive lumbar puncture. As a consequence, there is a growing demand for additional peripheral biomarkers in a more readily accessible sample material. Blood platelets, due to shared biochemical properties with neurons, can constitute an attractive alternative as discussed here. This review summarises potential platelet Alzheimer’s disease biomarkers, their role, implication, and alteration in the disease. For easy comparison of their performance, the Hedge effect size was calculated whenever data were available.

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Microdose Lithium Treatment Stabilized Cognitive Impairment in Patients with Alzheimer’s Disease

Cited by 85 publications

References 0 publications

RETRACTED ARTICLE:LISPRO mitigates β-amyloid and associated pathologies in Alzheimer’s mice

RETRACTED ARTICLE:LISPRO mitigates β-amyloid and associated pathologies in Alzheimer’s mice

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

Platelets, a reliable source for peripheral Alzheimer’s disease biomarkers?

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