Correction: Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease

Nunes, Marielza Andrade; Schöwe, Natália Mendes; Monteiro-Silva, Karla Cristina; Baraldi-Tornisielo, Ticiana; Souza, Suzzanna Ingryd Gonçalves; Balthazar, Janaina; Albuquerque, Marilia Silva; Caetano, Ariadiny Lima; Viel, Tânia Araújo; Buck, Hudson Sousa

doi:10.1371/journal.pone.0145695

Cited by 5 publications

(10 citation statements)

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“…Chronic (>15 months) microdose lithium administration has been suggested to stabilize memory impairment in AD patients (Nunes et al, 2013) and prevent neuropathology and cognitive decline in mice and rat models of AD with no observed toxicity (Nunes et al, 2015; Wilson et al, 2017). More recently LISPRO, a new ionic co-crystalized formulation of lithium salicylate and L-proline, has been reported to have improved brain penetrance and a safer pharmacokinetic profile over classical lithium chloride and carbonate salts (Habib et al, 2017).…”

Section: Future Perspectives: Combination Therapies Vs Lithium Treatmentioning

confidence: 99%

Molecular Mechanisms of Lithium Action: Switching the Light on Multiple Targets for Dementia Using Animal Models

Kerr

Bjedov

Sofola-Adesakin

2018

Front. Mol. Neurosci.

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Lithium has long been used for the treatment of psychiatric disorders, due to its robust beneficial effect as a mood stabilizing drug. Lithium’s effectiveness for improving neurological function is therefore well-described, stimulating the investigation of its potential use in several neurodegenerative conditions including Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s (HD) diseases. A narrow therapeutic window for these effects, however, has led to concerted efforts to understand the molecular mechanisms of lithium action in the brain, in order to develop more selective treatments that harness its neuroprotective potential whilst limiting contraindications. Animal models have proven pivotal in these studies, with lithium displaying advantageous effects on behavior across species, including worms (C. elegans), zebrafish (Danio rerio), fruit flies (Drosophila melanogaster) and rodents. Due to their susceptibility to genetic manipulation, functional genomic analyses in these model organisms have provided evidence for the main molecular determinants of lithium action, including inhibition of inositol monophosphatase (IMPA) and glycogen synthase kinase-3 (GSK-3). Accumulating pre-clinical evidence has indeed provided a basis for research into the therapeutic use of lithium for the treatment of dementia, an area of medical priority due to its increasing global impact and lack of disease-modifying drugs. Although lithium has been extensively described to prevent AD-associated amyloid and tau pathologies, this review article will focus on generic mechanisms by which lithium preserves neuronal function and improves memory in animal models of dementia. Of these, evidence from worms, flies and mice points to GSK-3 as the most robust mediator of lithium’s neuro-protective effect, but it’s interaction with downstream pathways, including Wnt/β-catenin, CREB/brain-derived neurotrophic factor (BDNF), nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and toll-like receptor 4 (TLR4)/nuclear factor-κB (NFκB), have identified multiple targets for development of drugs which harness lithium’s neurogenic, cytoprotective, synaptic maintenance, anti-oxidant, anti-inflammatory and protein homeostasis properties, in addition to more potent and selective GSK-3 inhibitors. Lithium, therefore, has advantages as a multi-functional therapy to combat the complex molecular pathology of dementia. Animal studies will be vital, however, for comparative analyses to determine which of these defense mechanisms are most required to slow-down cognitive decline in dementia, and whether combination therapies can synergize systems to exploit lithium’s neuro-protective power while avoiding deleterious toxicity.

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Section: Future Perspectives: Combination Therapies Vs Lithium Treatmentioning

confidence: 99%

Molecular Mechanisms of Lithium Action: Switching the Light on Multiple Targets for Dementia Using Animal Models

Kerr

Bjedov

Sofola-Adesakin

2018

Front. Mol. Neurosci.

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“…The preservation of neuronal density is a typical characteristic of the treatment with the lithium in low-dose, as we have been observed this effect in the hippocampus of 16-months-old transgenic mice model for AD [ 14 ] and 10-months-old male SAMP-8 [ 13 ] with the chronic treatment with lithium. Also the treatment of ex-vivo hippocampus slices with lithium in low-dose also evidenced the neuroprotection observed in vivo [ 36 ].…”

Section: Discussionmentioning

confidence: 81%

“…Alzheimer’s disease (AD) is still the most important cause of dementia worldwide, but until today that is no cure for this devastating disease. In the last years, our research team showed the beneficial effects of the treatment with microdose lithium for memory maintenance and neuroprotection in a transgenic mice model of AD [ 14 ], but the cellular mechanisms of this low dosage of lithium are still lacking.…”

Section: Discussionmentioning

confidence: 99%

“…Microdose lithium is being considered as a disease-modifying strategy both in human and animal observations (Nunes et al, 2013, 2015a; Relaño-Ginés et al, 2018), which turns it into a hope for treatment of these diseases, along with lifestyle changes, like the practice of physical activity and the environmental enrichment, strategies that protect the brain from the development of AD and others neurodegenerative diseases (Toricelli et al, 2020; Malerba et al, 2021). In previous works our research team showed that effects of this low dosage are seen when a physiological/pathological disturbance is present, as is observed in AD mice models [ 14 ]. In this way, there was no effect of low dosage lithium in wild-type mice, unless for an anxiety reduction (Nunes et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Lithium, in the form of lithium carbonate (Li 2 CO 3 ), was dissolved in water and administered ad libitum . The dose used was the same as published by our research team before for mice treatment [ 13 , 14 ] and proportional to that used in a previous manuscript with Alzheimer’s disease’s patients [ 15 ]. The dose used in mice corresponds to 1.5 mg of lithium carbonate/day or 0.006 mEq of lithium/kg.…”

Section: Methodsmentioning

confidence: 99%

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Microdose lithium improves behavioral deficits and modulates molecular mechanisms of memory formation in female SAMP-8, a mouse model of accelerated aging

Pereira,

Pinto,

Malerba

et al. 2024

PLoS ONE

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Alzheimer’s disease (AD) is the most common neuronal disorder that leads to the development of dementia. Until nowadays, some therapies may alleviate the symptoms, but there is no pharmacological treatment. Microdosing lithium has been used to modify the pathological characteristics of the disease, with effects in both experimental and clinical conditions. The present work aimed to analyze the effects of this treatment on spatial memory, anxiety, and molecular mechanisms related to long-term memory formation during the aging process of a mouse model of accelerated aging (SAMP-8). Female SAMP-8 showed learning and memory impairments together with disruption of memory mechanisms, neuronal loss, and increased density of senile plaques compared to their natural control strain, the senescence-accelerated mouse resistant (SAMR-1). Chronic treatment with lithium promoted memory maintenance, reduction in anxiety, and maintenance of proteins related to memory formation and neuronal density. The density of senile plaques was also reduced. An increase in the density of gamma-aminobutyric acid A (GABAA) and α7 nicotinic cholinergic receptors was also observed and related to neuroprotection and anxiety reduction. In addition, this microdose of lithium inhibited the activation of glycogen synthase kinase-3beta (GSK-3β), the classical mechanism of lithium cell effects, which could contribute to the preservation of the memory mechanism and reduction in senile plaque formation. This work shows that lithium effects in neuroprotection along the aging process are not related to a unique cellular mechanism but produce multiple effects that slowly protect the brain along the aging process.

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Stereological investigation of the CA1 pyramidal cell layer in untreated and lithium-treated 3xTg-AD and wild-type mice

Schaeffer

Catanozi

West

et al. 2017

Annals of Anatomy - Anatomischer Anzeiger

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Correction: Chronic Microdose Lithium Treatment Prevented Memory Loss and Neurohistopathological Changes in a Transgenic Mouse Model of Alzheimer's Disease

Cited by 5 publications

References 1 publication

Molecular Mechanisms of Lithium Action: Switching the Light on Multiple Targets for Dementia Using Animal Models

Molecular Mechanisms of Lithium Action: Switching the Light on Multiple Targets for Dementia Using Animal Models

Microdose lithium improves behavioral deficits and modulates molecular mechanisms of memory formation in female SAMP-8, a mouse model of accelerated aging

Stereological investigation of the CA1 pyramidal cell layer in untreated and lithium-treated 3xTg-AD and wild-type mice

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