Prion diseases are neurodegenerative disorders that can affect humans and animals. The underlying event is a conformational change of the normal cellular prion protein (PrPC) into an aberrant isoform termed PrP-scrapie (PrPSc). PrPSc is thought to lead to neurodegeneration and activation of glial cells. Scrapie infection of neuroblastoma cells was shown to increase the expression of insulin receptor (IR). Additionally, a marked reduction of 125I-insulin binding sites was observed. Insulin stimulation showed alteration in both IR β-subunit tyrosine phosphorylation and extracellular signal regulated kinase-2 (ERK2) activity.  Furthermore, scrapie infection was shown to increase insulin-like growth factor-1(IGF-1) receptor (IGF-1R) expression, although the number of 125I-IGF-1-binding sites was reduced. Also binding affinity of 125I-IGF-1 to its receptor was reduced, and tyrosine phosphorylation of IGF-1R-β-subunit in response to IGF-1 was altered. The increased levels of neurotrophic receptors might represent a neuroprotective response to prion infection. However, scrapie infection instead leads to decreased function, decreased levels of functional receptors, or both, which could promote neurodegeneration in prion diseases, through attenuated neurotrophic support. In BV-2 microglial cells, LPS-induced iNOS (inducible nitric oxide synthase) expression and subsequent NO production were mainly mediated through c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway. Antioxidant treatment indicates that oxidative suppressing mechanism(s) acts on JNK pathway possibly as a regulatory mechanism controlling the NO levels. The JNK pathway was also shown to play an important role in the survival of BV-2 cells. We show that BV-2 cells are protected from ongoing apoptosis by pro-survival activity mediated both by the JNK and p38 MAPK pathway during LPS-induced inflammation. This is very interesting findings since it is important for microglia to respond properly to a pathogen, without themselves being affected and undergo apoptosis.

Chronic ethanol exposure results in neuroadaptations that drive the progression of an alcohol use disorder (AUD). One such driving force is alcohol-induced neurodegeneration. Neuroinflammation has been proposed as a mechanism underlying this damage. Although neuroinflammation is a physiological response to damage, overactivation of its pathways can lead to neurodegeneration. A hallmark indicator of neuroinflammation is microglial activation, but microglial activation is a heterogeneous continuum of phenotypes that can promote or inhibit neuroinflammation. Furthermore acute microglial activation is necessary to restore homeostasis, but prolonged activation can exacerbate damage. The diversity of microglia makes both the level and timecourse of activation vital to understanding their role in damage and/or recovery. The current set of experiments examines the effects of ethanol on microglia within the hippocampus and entorhinal cortex in a binge model of alcohol-induced neurodegeneration. In the first set of experiments, the phenotype of microglia activation was assessed using Raivich’s 5-stages of activation that separates pro- and anti-inflammatory forms of microglia. Morphological and functional assessments suggest that ethanol does not elicit classical microglial activation but instead induces partially activated microglia. In the second set of experiments, the earliest signs of microglial activation were determined to understand the initiation of microglial activation. Experiments indicated that activation occurred subsequent to previous evidence of neuronal damage; however, activation was accompanied by a loss of microglia and the discovery of dystrophic microglia. The final set of experiments examined whether alcohol-induced partial activation of microglia would show a differential response with further alcohol exposure. Experiments showed that animals previously exposed to ethanol showed a greater response to a second ethanol insult. Overall, these studies suggest that although alcohol may initially interrupt the normal microglia response, during abstinence from ethanol a partial activation phenotype appears that may contribute to recovery. Once activated, however, data suggest that these microglia are primed and upon subsequent exposure show an increased response. This heterogeneous microglial response with respect to time does not necessarily reflect a neuroinflammatory response that would be neurodegenerative but does imply that chronic ethanol consumption affects the normal neuroimmune system.