Minocycline, a derivative of the antibiotic tetracycline, displays neuroprotective properties in various models of neurodegenerative diseases and is now used in clinical trials, because of its relative safety and tolerability. Minocycline passes the blood-brain barrier and is presumed to inhibit microglial activation. In Alzheimer's disease brain, a number of proteins, including serum amyloid P component (SAP) and complement factors such as C1q, accumulate in amyloid beta (Abeta) plaques. In a previous study, SAP and C1q were found to be required for clustering of activated microglia in Abeta plaques. Furthermore, SAP and C1q enhanced Abeta fibril formation and Abeta mediated cytokine release by human microglia in vitro. In the present study, we report that tetracycline and minocycline dose-dependently reduce TNF-alpha and IL-6 release by adult human microglia upon stimulation with a combination of Abeta, SAP, and C1q. In addition, minocycline and to a lesser extent tetracycline inhibit fibril formation of Abeta as determined in a thioflavin-S-based fluorescence test. This inhibitory effect was observed with Abeta alone as well as with Abeta in combination with SAP and C1q. Our data suggest that minocycline and tetracycline at tolerable doses can inhibit human microglial activation. This activity in part is exerted by inhibition of (SAP and C1q enhanced) Abeta fibril formation.
"In primary cortical neurons, minocycline was shown to reduce caspase-3 activation and lowered generation of caspase 3-cleaved tau fragments . Recently, minocycline was shown to protect against Aβ-induced cell death and prevent fibrillization of Aβ in vitro, reduce iNOS levels , prevent Aβ deposition and cognitive decline in APP transgenic mice [134,135] by reducing BACE1 levels , 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 . "
[Show abstract][Hide abstract] 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.
Journal of Neuroinflammation 02/2014; 11(1):25. DOI:10.1186/1742-2094-11-25 · 5.41 Impact Factor
"The application of Rac1 inhibitor NSC23766 to hippocampal slices from Fmr1 KO mice reduced long-term depression, suggesting that modulation of RAC1 could ameliorate synaptic transmission deficits associated with FXS . Minocycline, a tetracycline derivative, inhibits Aβ-induced neuronal cell death, Aβ fibril formation, and microglial activation [102,103]. Minocycline can also reverse FXS phenotypes, including dendritic spine immaturity . The latter therapies represent more targeted approaches, and as there are currently no approved glutamatergic inhibitors for use in humans, treatments that focus on mGluR5, RAC1 or APP may provide safe, effective means of ameliorating the behavioral deficits of autism. "
[Show abstract][Hide abstract] ABSTRACT: Candidate genes associated with idiopathic forms of autism overlap with other disorders including fragile X syndrome. Our laboratory has previously shown reduction in fragile X mental retardation protein (FMRP) and increase in metabotropic glutamate receptor 5 (mGluR5) in cerebellar vermis and superior frontal cortex (BA9) of individuals with autism.
In the current study we have investigated expression of four targets of FMRP and mGluR5 signaling - homer 1, amyloid beta A4 precursor protein (APP), ras-related C3 botulinum toxin substrate 1 (RAC1), and striatal-enriched protein tyrosine phosphatase (STEP) - in the cerebellar vermis and superior frontal cortex (BA9) via SDS-PAGE and western blotting. Data were analyzed based on stratification with respect to age (children and adolescents vs. adults), anatomic region of the brain (BA9 vs. cerebellar vermis), and impact of medications (children and adolescents on medications (n = 4) vs. total children and adolescents (n = 12); adults on medications (n = 6) vs. total adults (n = 12)).
There were significant increases in RAC1, APP 120 kDa and APP 80 kDa proteins in BA9 of children with autism vs. healthy controls. None of the same proteins were significantly affected in cerebellar vermis of children with autism. In BA9 of adults with autism there were significant increases in RAC1 and STEP 46 kDa and a significant decrease in homer 1 vs. controls. In the vermis of adult subjects with autism, RAC1 was significantly increased while APP 120, STEP 66 kDa, STEP 27 kDa, and homer 1 were significantly decreased when compared with healthy controls. No changes were observed in vermis of children with autism. There was a significant effect of anticonvulsant use on STEP 46 kDa/beta-actin and a potential effect on homer 1/NSE, in BA9 of adults with autism. However, no other significant confound effects were observed in this study.
Our findings provide further evidence of abnormalities in FMRP and mGluR5 signaling partners in brains of individuals with autism and open the door to potential targeted treatments which could help ameliorate the symptoms of autism.
"It is often termed an inhibitor of microglial activation, and the list of inflammatory cytokines it down-regulates, in brain and elsewhere , includes TNF and IL-1␤ (Célérier et al., 1996; Lee et al., 2004; Suk, 2004; Wang et al., 2005a). Consistent with the overarching pathway central to this review , minocycline shows experimental promise as a treatment, complementary to the others we discuss, for the various manifestations of excess production of these cytokines in the brain (Familian et al., 2006; Seabrook et al., 2006; Choi et al., 2007; Fan et al., 2007; Noble et al., 2009). A human AD trial with minocycline is under way (http://clinicaltrials.gov/ct2/show/NCT01463384). "
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