A feasibility and tolerability study of lithium in Alzheimer's disease

Macdonald, Alastair; Briggs, Kate; Poppe, Michaela; Higgins, Andrea; Velayudhan, Latha; Lovestone, Simon

doi:10.1002/gps.1964

Cited by 138 publications

(103 citation statements)

References 43 publications

(40 reference statements)

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“…Our current study might help explain the failure of trials of lithium for AD 40,98 and amyotrophic lateral sclerosis, b99, 100, 101 both diseases where elevated iron in the affected tissue has been implicated in pathogenesis. 52,102,103,104 Despite the neurotoxicity in mice that our studies have elaborated, clinical lithium pharmacotherapy has predominantly neurotrophic benefits in the treatment of bipolar disorder.…”

Section: Discussionmentioning

confidence: 84%

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

et al. 2016

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Lithium is a first-line therapy for bipolar affective disorder. However, various adverse effects, including a Parkinson-like hand tremor, often limit its use. The understanding of the neurobiological basis of these side effects is still very limited. Nigral iron elevation is also a feature of Parkinsonian degeneration that may be related to soluble tau reduction. We found that magnetic resonance imaging T 2 relaxation time changes in subjects commenced on lithium therapy were consistent with iron elevation. In mice, lithium treatment lowers brain tau levels and increases nigral and cortical iron elevation that is closely associated with neurodegeneration, cognitive loss and parkinsonian features. In neuronal cultures lithium attenuates iron efflux by lowering tau protein that traffics amyloid precursor protein to facilitate iron efflux. Thus, tauand amyloid protein precursor-knockout mice were protected against lithium-induced iron elevation and neurotoxicity. These findings challenge the appropriateness of lithium as a potential treatment for disorders where brain iron is elevated (for example, Alzheimer's disease), and may explain lithium-associated motor symptoms in susceptible patients.

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Section: Discussionmentioning

confidence: 84%

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

et al. 2016

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“…GSK-3 has also been suggested to participate in the pathogenesis of Alzheimer disease (AD) (9,10), as it is the predominant tau kinase in brain (11,12) and an important player in amyloid-β production and toxicity (13,14), and mice with increased GSK-3 activity mimic this disease (15,16). Accordingly, GSK-3 inhibitors, including lithium, have been postulated as a potential therapy for AD (17)(18)(19)(20)(21). However, clinical trials to assess the efficacy of chronic lithium for AD are hampered by the above-mentioned toxicity of lithium therapy, particularly in the elderly (19,22,23).…”

Section: Introductionmentioning

confidence: 99%

NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy

Gómez‐Sintes¹,

Lucas²

2010

J. Clin. Invest.

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Use of lithium, the mainstay for treatment of bipolar disorder, is limited by its frequent neurological side effects and its risk for overdose-induced toxicity. Recently, lithium has also been proposed as a treatment for Alzheimer disease and other neurodegenerative conditions, but clinical trials have been hampered by its prominent side effects in the elderly. The mechanisms underlying both the positive and negative effects of lithium are not fully known. Lithium inhibits glycogen synthase kinase-3 (GSK-3) in vivo, and we recently reported neuronal apoptosis and motor deficits in dominant-negative GSK-3-transgenic mice. We hypothesized that therapeutic levels of lithium could also induce neuronal loss through GSK-3 inhibition. Here we report induction of neuronal apoptosis in various brain regions and the presence of motor deficits in mice treated chronically with lithium. We found that GSK-3 inhibition increased translocation of nuclear factor of activated T cells c3/4 (NFATc3/4) transcription factors to the nucleus, leading to increased Fas ligand (FasL) levels and Fas activation. Lithium-induced apoptosis and motor deficits were absent when NFAT nuclear translocation was prevented by cyclosporin A administration and in Fas-deficient lpr mice. The results of these studies suggest a mechanism for lithium-induced neuronal and motor toxicity. These findings may enable the development of combined therapies that diminish the toxicities of lithium and possibly other GSK-3 inhibitors and extend their potential to the treatment of Alzheimer disease and other neurodegenerative conditions.

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“…Together with valproic acid (VPA), 3 a histone deacetylases inhibitor, lithium remains the most commonly used drug for mental diseases (1,2). Accumulating evidence indicates that lithium also plays a neuroprotective role in neurodegenerative diseases such as Alzheimer disease (3)(4)(5), Parkinson disease (6 -8), and Huntington disease (9,10). Moreover, lithium has been found to be a multifunctional ion in a variety of cellular processes including cell proliferation (11), the cell cycle, and cell apoptosis (12,13) as well as embryonic development (14) and tissue formation (15).…”

mentioning

confidence: 99%

Lithium Down-regulates Histone Deacetylase 1 (HDAC1) and Induces Degradation of Mutant Huntingtin

Zheng

Huang

et al. 2013

Journal of Biological Chemistry

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Background: Lithium and valproic acid (VPA) exhibit a robust neuroprotective and anti-tumor effects in neural cells and tumor cells. Results: Lithium significantly down-regulates HDAC1 at the translational level by targeting HDAC1 mRNA. Conclusion:The decrease in HDAC1 is essential for the lithium-mediated, autophagic degradation of mutant huntingtin. Significance: This report is the first demonstration that HDAC1 decreases in response to lithium treatment.

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A feasibility and tolerability study of lithium in Alzheimer's disease

Cited by 138 publications

References 43 publications

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy

Lithium Down-regulates Histone Deacetylase 1 (HDAC1) and Induces Degradation of Mutant Huntingtin

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