The phagocytic activity of microglia is attenuated by proinflammatory cytokines such as IFN, IL, and TNF, which most likely shifts microglia into the proinflammatory M state. A peptideshavethec apacitytoself ass emble, transforming from monomeric to oligomeric, and then to insoluble heavy aggregates.Interestingly, different forms of A peptides may induce different inflammatory profiles of microglia.In the hippocampus of PSMLAPPSL double transgenic AD mice, an agedependent phenotypic change of microglial activation is an active processing. M microglia with A phagocytic capabilities in AD mice at months of age can switch into M phenotypes at months of age, which is coincident with accumulated levels of soluble A oligomers. The YM positive and TNF negative microglia cells are exclusively located surrounding and infiltrating the A plaques. Furthermore, this M phenotype seems to maintain even at relative old ages, suggesting that activated microglia surrounding A plaques adopted an alternative phenotype, regardless of the age. In the mice of months old, microglial activation is expanded into hippocampal areas free of plaques, showing that classic M phenotypes producing cytotoxic effects to neurons. Proinflammatory factors IL and IFN as well as LPS suppress the microglial phagocytosis of fibrillar A peptides, which are antagonized by antiinflammatory cytokines including IL, IL, TGF, and IL both in vitro and in vivo. Activation of M microglia results in an increase of iNOS expression.Ablation of iNOS in the APPPS mice can protect the mice from plaque formation and premature mortality. However, in other reports, microglial activation by acute LPS treatment reduces A load in APP transgenic mice, which is prevented by cotreatment with dexamethasone. Thus in the closed in vivo system, the role of inflammatory cytokines impairing A clearance is still controversial, as seen not all consistent with the in vitro results.Antiinflammatory factors were believed to be promising Panthenol molecules in AD therapy.There was a reduction in A plaques and an improvement in spatial memory of APPPS mice months after the intrahippocampally injected AAV carrying IL while not IL. They showed that IL treatment attenuated soluble A uptake by microglia but does not affect aggregated A internalization by microglia or soluble A internalization by astrocytes. This shortterm focal IL expression led to reduced glia phagocytosis and acute suppression of glial clearance mechanisms.The acute incorporation of either proinflammatory or antiinflammatory factors might cause unwarranted effects.In most cases, microglia in AD patients may exhibit mixed activation phenotypes.Interestingly, the results are always correlated in those animal models and AD patients.Microarray analysis on brain samples from AD subjects shows upregulation of apoptotic and proinflammatory signaling represented by major histocompatibility complex class II, IFN, and IL elevation. The discrepancies of gene expression Trimethoprim patterns in different models and in different stages of disease suggest a very complicated cytokine environment in the brain and its role in modifying microglial responses to A plaques.Microglia might exhibit specific dominant phenotypes during a chronic neuroinflammatory process.Hence, understanding the sequence and timing of the alterations in MM phenotypes in AD is important.As another hallmark of AD, misfolded tau protein plays a crucial role in the formation of intracellular tangles, which is a driving force of neurofibrillary degeneration in AD or other diseases.