Mechanisms of iron induce neurodegeneration in alzheimer's disease : an in vitro study

Abstract

In degenerated brain regions of Alzheimer’s disease (AD), abnormally high levels of iron have been reported. At cellular levels, progressive iron accumulation by activated microglia has also been observed, but its significance remains elusive. Although it has not yet known that iron accumulation in AD brain is an initial event that causes neurodegeneration or a consequence of the disease process, recent evidences have been reported that mutation in the gene involved in iron absorption, HFE, increased brain iron accumulation and also associated with AD. These reports have opened the possibility that increased brain iron accumulation may be an initial event that contributes to neurodegeneration in AD. However, the mechanisms have not yet known. In this study, iron supplemented and lipopolysaccharide (LPS)-activated cultures of BV2 microglia was developed to mimic progressive iron accumulation by activated microglia and used to address the functional relationship between iron and microglial activation, which demonstrated to be partially mediated by glycogen synthase kinase-3β (GSK-3β). The results were shown that the presence of iron during microglial activation enhanced GSK-3β activity, the nuclear levels of NF-κB and subsequently increased the expression of matrix metalloproteinase-9 (MMP-9). The presence of iron during microglial activation also significantly enhanced the cytotoxic effects of microglial culture medium to neuroblastoma (NA) cells, when compared to that of microglia activated by LPS alone. The inhibiting of GSK-3β during the activation of microglia even in the presence of iron protected NA cells from the cytotoxic effects of these cell culture media. These results were consistent with decreased GSK-3β activity and nuclear levels of NF-κB, MMP-9, IL-1β, TNF-α and NO in these cultures. Furthermore, increased cellular iron levels in neuroblastoma cells transfected with H63D HFE variant also increased reactive oxygen species, decreased mitochondrial membrane potential and cytochrome c oxidase activity, markers of mitochondrial damage, increased GSK-3β activity, mitochondrial Aβ and neuronal apoptosis. The results in these studies suggest that the presence of iron appears to modify microglial activation and its associated neurotoxicity, which were partly due to the regulatory role of iron on GSK-3β activity. Moreover, increased cellular iron levels in HFE mutation might be a one factor that triggers the onset of neurodegeneration at least in part by increasing oxidative stress, GSK-3β activity, mitochondrial damage and neuronal apoptosis.