The major trigger in AD is the extracellular A oligomers, whereas the synuclein or SOD aggregation is mostly intracellular, which may play a greatest role after their release from injured or dead cells.Secondly, the regionally distributed A plaques also make the unevenly distribution of MM Sertraline hydrochloride microglia in the lesion area, which is different in PD and ALS.Thirdly, infiltrated peripheral macrophages or monocytes in AD are more often to penetrate into the CNS to help eliminate the extracellular oligomeric A or tau antigens. Those peripheral macrophages are also undergoing phenotypic switch that may compromise the role of microglia.Therefore, it is not easy to make a quick conclusion regarding the role of MM microglia in AD, considering the molecular mechanisms of M microglia are still less studied in this disease.The extra complexity arises from that M microglia might be also activated slightly in some models while not suppressed by M microglia along the disease pathogenesis.So far, the majority of studies on microglial phenotypes are focused on the various animal models, the indepth functions of microglial phenotype switch in neurodegenerative diseases especially in AD are still very open.Establishment of an animal model showing pathology that truly represents those neurodegenerative diseases especially progressive neuronal loss in human body may partially mitigate those discrepancies.In the aged brain, many microglia cells undergo various molecular and cellular changes and even morpho log icalfe a tu resindicativeof senes cence, su ch asfragmented cytoplasmic processes, rendering them lose the ability to protect the brain. It is also hypothesized as microglia dysfunction or dystrophic that provides initial evidence for the ageassociated changes in microglia.More importantly, aged microglia are also manifested by altered inflammatory profiles. Normal aging in the brain is accompanied by increasing number of proinflammatory mediators such as IL and IL while compromising IL level. Additionally, treatment with MPTP in aged mice can cause severer DA neuron loss and greater microglial activation in the SN. As the classical activation in the CNS is enhanced along aging, alternative activation appears to be mitigated, which is manifested by the reduction in the ILIL signaling pathway. Clinical therapy of neurodegenerative diseases faces numerous challenges with respect to timing, effic a cy, ands afety.Ta rgeting a nyoneofthev astproinflammatory mediators or pathways may not be efficacious, and the antiinflammatory strategy varies in different diseases.Early stage intervention with drugs targeting dysregulated proinflammatory cytokine production might be therapeutically beneficial.A small molecule named MW has been tested during two distinct but overlapping therapeutic time windows at the early pathological stage in APPPS transgenic mice.MW treatment attenuates the microglial activation and the production of proinflammatory cytokines in the cortex, which protects from synaptic dysfunction implicated in learning and memory. As Imiquimod stated above, it might be interesting to manipulate microglia phenotypes from cytotoxic to neuroprotective by drug treatment or genetic modification.To be clinically effective, targeting MM balance also depends on the time window, since the timing, stages, and severity of diseases are critically associated with the changing microglial activation states. Antiinflammatory therapies will have to gain access to the CNS; it is not realistic that cytokines are used to modulate microglia polarization because most of the cytokines cannot enter brain tissue.