Activated microglia have been frequently present in the proximity of neurofibrillary tangles and tanglebearing neurons in the hippocampus of AD patients, as well as various tau transgenic models at early and late stages of tangle formation, indicating a close relationship between inflammatory response and tau neurofibrillary lesions. Tau oligomers and fibrils which were induced by arachidonic acid in vitro can augment the production of nitrites and proinflammatory cytokine IL in microglia cells. In early stages of tau structural metamorphosis, some proinflammatory cytokines such as IL, IL and TNF, as well as fractalkine can modify tau phosphorylation patterns and alter the structure and function of tau proteins. Enhanced proinflammatory reasch Xylitol activation of microglia by disruption of CXCR, an antiinflammatory CXCL receptor, accelerates tangle formation. Interestingly, in the affected spinal cord region, JNPL mutant mice showed accumulation of alternatively activated microglia. The common hallmark shared by familial and sporadic ALS patients is neuroinflammation, characterized by microglialastroglial activation and infiltration of peripheral T cells.Mutant TDPMV evoked robust microglial activation around diseased motoneurons in the ventral horns. Microglia expressing higher amounts of TDP produced more proinflammatory cytokines and neurotoxic mediators after stimulation with LPS or ROS, due to the activation of p subunit of NFB that interacts with TDP as a coactivator. Compared to T D P, S O D isextensivelystudiedintheimmunopathogenesis of ALS.Intracellular and extracellular mSOD employs different pathways to enhance the production of ROS and exaggerates the proinflammatory signaling in microglia. Whereas treatment with IL suppresses M microglial activation by reducing the release of ROS and promotes an M phenotype by enhancing IGFI purchase Xylitol secretion that improves motoneuron survival. Following activation with LPS, primary microglia isolated from mSODGA transgenic mice are more neurotoxic than activated wildtype microglia, due to the increased production of superoxide, NO, and proinflammatory cytokines IL and TNF, as well as the less release of IGFI. A lack or reduction of mSOD expression in microglia could slow disease progression and prolong the survival of mSODGA or mSODGR mice. Microglia in mSODGA mouse model appear to switch from an M microglial phenotype observed at the beginning of pathology to an M phenotype as disease progresses with increasing expressions of CD, iNOS, and the NADPH oxidase isoform NOX and proinflammatory cytokines, including TNF, IL, and IL. This may indicate the diminished function of neuroprotective microglia in the late disease stage.Deletion of the proinflammatory factors such as NOX rescues almost three times motoneuron death in the spinal cords of mSODGA mice. Ablation of NFB signaling in microglia rescues motoneurons in vitro and extends survival in mSODGA mice. Similarly, administration of minocycline delays the pathogenesis of mSODGA mice by selectively attenuating the induction of M microglia markers during the progressive phase, without affecting the transient enhancement of expression of M microglia markers at the early onset stage. Collectively, microglia have both neuroprotective and cytotoxic functions in ALS.In the first response, M microglia may augment a neuroprotective effect, and then following sustained neuronal stress and signaling, a transformation of microglial phenotypes happens.Thus, there exist various controversial results that link MM microglia switch and disease development.