ABSTRACT
Microglia are the principal immune effectors in brain and participate in a series ofneurodegenerative diseases. The microglial shapes are highly plastic. The morphology is closely related with their activation status and biological functions. Cerebral ischemia could induce microglial activation, and microglial activation is subjected to precise regulation. Microglia could play either protective or neurotoxic roles in cerebral ischemia. Therefore, regulating the expression of receptors or protein molecules on microglia, inhibiting the excessive activation of microglia and production of pro-inflammatory factors, promoting the release of neuroprotective substances might be beneficial to the treatment of cerebral ischemia. The study about relationship between microglia and cerebral ischemia will shed a light on the treatment of cerebral ischemia. This paper is a review of microglial activation and regulation during cerebral ischemia as well as related therapeutic methods.
Subject(s)
Brain Ischemia/metabolism , Brain Ischemia/pathology , Microglia/metabolism , Microglia/physiology , Animals , Class Ib Phosphatidylinositol 3-Kinase/metabolism , Humans , Inflammation/metabolism , Microglia/cytology , Microglia/drug effects , Neuroprotective Agents/pharmacology , Nitric Oxide Synthase/metabolism , Receptors, Purinergic P2X7/metabolism , Regeneration , TNF-Related Apoptosis-Inducing Ligand/metabolism , Toll-Like Receptors/metabolismABSTRACT
Alzheimer's disease (AD) is the most common cause of dementia worldwide and mainly characterized by the aggregated ß-amyloid (Aß) and hyperphosphorylated tau. FLZ is a novel synthetic derivative of natural squamosamide and has been proved to improve memory deficits in dementia animal models. In this study, we aimed to investigate the mechanisms of FLZ's neuroprotective effect in APP/PS1 double transgenic mice and SH-SY5Y (APPwt/swe) cells. The results showed that treatment with FLZ significantly improved the memory deficits of APP/PS1 transgenic mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Aß accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study showed that FLZ interfered APP processing, i.e., FLZ decreased ß-amyloid precursor protein (APP) phosphorylation, APP-carboxy-terminal fragment (APP-CTF) production and ß-amyloid precursor protein cleaving enzyme 1 (BACE1) expression. These results indicated that FLZ reduced Aß production through inhibiting amyloidogenic pathway. The mechanistic study about FLZ's inhibitory effect on tau phosphorylation revealed t the involvement of Akt/glycogen synthase kinase 3ß (GSK3ß) pathway. FLZ treatment increased Akt activity and inhibited GSK3ß activity both in vivo and in vitro. The inhibitory effect of FLZ on GSK3ß activity and tau phosphorylation was suppressed by inhibiting Akt activity, indicating that Akt/GSK3ß pathway might be the possible mechanism involved in the inhibitory effect of FLZ on tau hyperphosphorylation. These results suggested FLZ might be a potential anti-AD drug as it not only reduced Aß production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3ß.