Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Department of Pharmacology, College of Medicine, National Creative Research Initiative Center for Alzheimer's Dementia and Neuroscience Research Institute, MRC, Seoul National University, Seoul, South Korea.
Neuropsychopharmacology (Impact Factor: 7.05). 12/2007; 32(11):2393-404. DOI: 10.1038/sj.npp.1301377
Source: PubMed


Minocycline is a semi-synthetic tetracycline antibiotic that effectively crosses the blood-brain barrier. Minocycline has been reported to have significant neuroprotective effects in models of cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. In this study, we demonstrate that minocycline has neuroprotective effects in in vitro and in vivo Alzheimer's disease models. Minocycline was found to attenuate the increases in the phosphorylation of double-stranded RNA-dependent serine/threonine protein kinase, eukaryotic translation initiation factor-2 alpha and caspase 12 activation induced by amyloid beta peptide1-42 treatment in NGF-differentiated PC 12 cells. In addition, increases in the phosphorylation of eukaryotic translation initiation factor-2 alpha were attenuated by administration of minocycline in Tg2576 mice, which harbor mutated human APP695 gene including the Swedish double mutation and amyloid beta peptide(1-42)-infused rats. We found that minocycline administration attenuated deficits in learning and memory in amyloid beta peptide(1-42)-infused rats. Increased phosphorylated state of eukaryotic translation initiation factor-2 alpha is observed in Alzheimer's disease patients' brains and may result in impairment of cognitive functions in Alzheimer's disease patients by decreasing the efficacy of de novo protein synthesis required for synaptic plasticity. On the basis of these results, minocycline may prove to be a good candidate as an effective therapeutic agent for Alzheimer's disease.

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Available from: Seonghan Kim, Aug 20, 2014
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    • "Rifampicin , an antibiotic, enhances Ab clearance by inducing LRP1 expression at the blood-brain barrier (Qosa et al., 2012). Another antibiotic, minocycline (Choi et al., 2007), and angiotensin receptor blockers (Li et al., 2010) are able to attenuate the progression of dementia, but there is not yet direct evidence that they target the Ab clearance machinery. We tested the reference compounds on NCSMCs cultured at 1% oxygen and found that statins and rifampicin upregulated the gene and protein expressions of lipoprotein receptors (Figures 4A and 4B). "
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    ABSTRACT: There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (Aβ) accumulation is evident in a majority of aged people and patients with cerebral amyloid angiopathy. Here, we leverage human pluripotent stem cells to generate vascular smooth muscle cells (SMCs) from neural crest progenitors, recapitulating brain-vasculature-specific attributes of Aβ metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest-derived SMCs to mediate Aβ uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to Aβ clearance by suppressing LRP1 expression. This enabled us to develop an assay of Aβ uptake by using the neural crest-derived SMCs with hypoxia as a stress paradigm. We then tested several vascular protective compounds in a high-throughput format, demonstrating the value of stem-cell-based phenotypic screening for novel therapeutics and drug repurposing, aimed at alleviating amyloid burden.
    Full-text · Article · Oct 2014 · Cell Reports
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    • "M inocycline is a tetracycline possessing anti-inflammatory properties independent of its antimicrobial action (Stirling et al., 2005). Adult animal models indicate that minocycline is beneficial and protective in several pathological conditions (Chen et al., 2000; Choi et al., 2007; Du et al., 2001; Nikodemova et al., 2010; Yrjanheikki et al., 1998) partly by inhibiting activation of microglial cells (MGs), the resident macrophages of the central nervous system (CNS). "
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    ABSTRACT: Minocycline, a tetracycline derivative, is known to exert neuroprotective effects unrelated to its antimicrobial action. In particular, minocycline prevents microglial activation in pathological conditions and consequently reduces the production of proinflammatory factors contributing to the propagation of diseases. Accumulative evidence indicates that microglial cells contribute to the maturation of neuronal and synaptic networks during the normal development of the central nervous system (CNS) and that perinatal inflammation is a known risk factor for brain lesions. Although minocycline has been used to infer microglia functions during development, mechanisms by which this tetracycline derivative affect the immature CNS have not been analyzed in detail. In this study, we demonstrate that minocycline administration during the first postnatal week of development has paradoxical effects on microglia phenotype and on neuronal survival in the mouse somatosensory cortex. Using a combination of immunohistochemistry and electrophysiology, we show that intraperitoneal injections of minocycline between postnatal days 6 and 8 affect distribution, morphology, and functional properties of microglia cells of the whisker-related barrel cortex, leading to the development of a phenotype resembling that of microglia activated in pathological conditions. Minocyline also induced a massive cell death that developed faster than changes in microglia phenotype, suggesting that the latter is a consequence of the former. Finally, cell death and microglial activation were not observed when minocycline treatment was postponed by only 2 days (i.e., between postnatal days 8 and 10). These observations call into question the use of tetracycline derivatives during CNS development to study microglia or to reduce perinatal inflammation. GLIA 2013;
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    • "In primary cortical neurons, minocycline was shown to reduce caspase-3 activation and lowered generation of caspase 3-cleaved tau fragments [132]. Recently, minocycline was shown to protect against Aβ-induced cell death and prevent fibrillization of Aβ in vitro[133], reduce iNOS levels [134], prevent Aβ deposition and cognitive decline in APP transgenic mice [134,135] by reducing BACE1 levels [134], inhibit neuronal death and attenuate learning and memory deficits following administration of Aβ in rats [136,137]. In addition, treatment of a tau model with minocycline resulted in reduced levels of tau phosphorylation and insoluble tau aggregates [132]. "
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    ABSTRACT: Over the past decade the process of inflammation has been a focus of increasing interest in the Alzheimer's disease (AD) field, not only for its potential role in neuronal degeneration but also as a promising therapeutic target. However, recent research in this field has provided divergent outcomes, largely due to the use of different models and different stages of the disease when the investigations have been carried out. It is now accepted that microglia, and possibly astrocytes, change their activation phenotype during ageing and the stage of the disease, and therefore these are important factors to have in mind to define the function of different inflammatory components as well as potential therapies. Modulating inflammation using animal models of AD has offered the possibility to investigate inflammatory components individually and manipulate inflammatory genes in amyloid precursor protein and tau transgenics independently. This has also offered some hints on the mechanisms by which these factors may affect AD pathology. In this review we examine the different transgenic approaches and treatments that have been reported to modulate inflammation using animal models of AD. These studies have provided evidence that enhancing inflammation is linked with increases in amyloid-beta (Abeta) generation, Abeta aggregation and tau phosphorylation. However, the alterations on tau phosphorylation can be independent of changes in Abeta levels by these inflammatory mediators.
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