Yeast unfolds the road map toward alpha-synuclein-induced cell death.

The budding yeast Saccharomyces cerevisiae has contributed significantly to our current understanding of eukaryotic cell biology. It served as a tool and model for unraveling the molecular basis of a wide variety of cellular phenomena, which seem to be conserved in other organisms. During the last decade, yeast has also extensively been used to study the mechanisms underlying several human diseases, including age-associated neurodegenerative disorders, such as Parkinson's, Huntington's and Alzheimer's disease. In this review, we focus on a yeast model for synucleinopathies and summarize recent studies that not only provided new clues on how the misfolding of alpha-synuclein (alpha-syn) triggers toxicity and eventually cell death, but that also led to the identification of conserved suppressor proteins, which are effective in protecting cells, including neurons, from the alpha-syn-induced cytotoxicity.

The inflammatory aspects of Chlamydia pneumoniae-induced brain infection.

The importance of inflammation in the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease, is increasingly being recognized. Although amyloid-beta is considered to be one of the main initiators of these inflammatory processes, some reports suggest that brain infections may also contribute or even initiate the neuroinflammation. One of the best studied pathogens that might be involved in this phenomenon is the herpes simplex virus, but more recently the obligate intracellular respiratory Gram-negative bacterium, Chlamydia pneumoniae, has also been associated with Alzheimer's disease. The present article discusses recent data on the role of C. pneumoniae infection in neuroinflammation and its potential contribution to the pathogenesis of Alzheimer's disease.

Inflammatory responses following Chlamydia pneumoniae infection of glial cells.

Recently, infections have been implicated in the pathogenesis of Alzheimer's disease. Apart from the direct effects of pathogens, it can be hypothesized that inflammatory mechanisms, such as the production of pro-inflammatory mediators by resident glia, may result in neurotoxicity. Here, we examined the inflammatory responses in murine microglial cell (MMC) and murine astrocyte cell (MAC) lines following infection with Chlamydia pneumoniae (Cpn), a pathogen that has recently been associated with Alzheimer's disease. Furthermore, we determined whether these inflammatory responses are sufficient to cause neuronal cell death in vitro. MMCs and MACs were infected with Cpn. Subsequently, various chemo- and cytokines were determined in the culture supernatant fluid of infected/control cells at different time points post-infection. Significantly higher levels of monocyte chemoattractant protein 1, interleukin (IL)-6, tumour necrosis factor (TNF)-alpha and IL-1beta were found in supernatant fluids of infected MMCs compared with controls. In contrast, in the supernatant fluid of infected MACs, only monocyte chemoattractant protein 1 and IL-6 displayed significantly higher levels compared with controls. Moreover, neurotoxicity was examined up to 72 h after transferring the conditioned supernatant fluid to a neuronal cell layer. No neuronal cell death was observed when supernatant fluids from infected/mock-treated MACs were transferred. However, when neurones were exposed to conditioned supernatant fluid from infected MMCs, a significant increase in cell death was observed compared with mock. Furthermore, adding neutralizing antibodies against IL-6 and TNF-alpha to that conditioned supernatant fluid prevented neuronal cell death by approximately 50%. In conclusion, these data suggest that Cpn infection results in a pro-inflammatory milieu, particularly by activating MMCs, that ultimately results in neurodegeneration with prominent roles for both IL-6 and TNF-alpha.