Microglial Responses in Degenerative CNS Diseases

A pathogenic role of microglia has been suggested in degenerative CNS diseases, such as Alzheimer's disease (AD) and Parkinson's disease, that are characterized by selective loss of neurons in distinct regions of the brain. These conditions lack an overt inflammatory response, but microglia are activated at sites of neuronal degeneration. AD is characterized pathologically by the presence of insoluble structures in the cerebral cortex that represent either extracellular plaques consisting of amyloid-b protein (Ab) deposits or neurofibrillary tangles within nerve cell bodies. In AD brain microglial cells accumulate in the center of plaques and in regions of perivascular deposits of Ab. Further examination of the relation of microglial activation to different stages of plaque development revealed a preferential association of activated MHC class II-positive microglia with diffuse amyloid deposits and of enlarged phagocytic microglia with amyloid plaques. This strong association has been commonly interpretated as a beneficial microglial attempt to phagocytose and remove neurotoxic Ab. In fact, microglia can internalize Ab fibrills by scavenger receptors, but the rate of Ab degradation is limited and the cells appear to be subsequently overwelmed by the amount of Ab present. As an alternative possibility, activated microglia have been suggested to contribute to neurotoxicity. In support of this view, Ab in culture together with the cytokine IFN-g activated microglia to produce reactive nitrogen intermediates and TNF-a. This process led to neuronal cell injury in vitro. Treatment of microglia with a secreted derivate of b-amyloid precursor protein (APP) led to activation of the transcription factor NF-kB with ensuing induction of IL-1b and inducible NOS. Taken together, these findings indicate that b-APP can activate microglia and enhance their neuro-toxicity.

The importance of microglial activation in degenerative CNS diseases has further been highlighted in an animal model of globoid cell leukodystrophy (GLD). GLD is a severe demyelinating disorder of the CNS. It is characterized by an increased number of MHC class II-expressing microglia/macrophages in the CNS but no T cell infiltration. Twitcher mice serve as an animal model for GLD. Mating twitcher mice with MHC class II-negative knockout mice led to a profound clinical improvement accompanied by reduced numbers of microglia/macrophages in the CNS in comparison to MHC class II-positive littermates. This points to a pathophysiological role of microglial MHC class II molecules in neurodegeneration independent of a T cell response. The underlying molecular mechanisms are unknown.

Breaking Bulimia

Breaking Bulimia

We have all been there: turning to the refrigerator if feeling lonely or bored or indulging in seconds or thirds if strained. But if you suffer from bulimia, the from time to time urge to overeat is more like an obsession.

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