Studies On Astrocyte In The Pathogenesis Of Alzheimer's Disease And Experimental Anti-inflammatory Treatment

Astrocytes appear to be important mediators in the clearance of amyloid beta(A?),the key component of senile plaques characteristic of Alzheimer's disease(AD).A?-degrading proteases such as neprilysin(NEP),insulin-degrading enzyme(IDE),endothelin-converting enzyme(ECE)have been widely studied to be able to degrade potentially neurotoxic A?.In this study,we aimed to investigate the roles of astrocyte and A?-degrading proteases and their relationship in the pathogenetic course of AD.Immunohistochemical staining of cortical tissue from NCI,MCI and AD,as well as APP/PS1 transgenic mice by antibody to GFAP and NEP showed the alternation in immunoreactivity of GFAP and NEP at various stages of AD.Western blot analysis showed increasing expression of NEP in the process of A? clearance by cultured astrocytes.Immunofluorescence staining on C6 rat glioma cells showed the intracellular distribution of NEP,IDE and ECE was co-located with late endosomes in astrocytes.Our data from human subjects and animal models indicated that astrocyte and NEP might be two critical factors on the onset of AD and there was a positive correlation between NEP and GFAP immunoreactivity levels in cortex of AD brains.In addition,NEP was involved in the in the process of A? clearance by cultured astrocytes in vitro.Besides,our study found late endosomes were related to A?-degrading proteases such as NEP,IDE and ECE in astrocyte.Meanwhile,inflammation in the CNS has been increasingly demonstrated as a prominent hallmark in AD,which is closely related to astrocytes.(+)-2-(1-hydroxyl-4-oxocyclohexyl)ethyl caffeate(HOEC),a caffeic ester isolated as a major constituent from lncarvillea mairei var granditlora(Wehrhahn)Grierson,is an anti-inflammatory compound.In this study,we aimed to determine the alteration in the capacity of clearing A? by cultured astrocytes from AD model mice and exhibit the protective effect on injured or aged astrocytes by restoring their capacity to respond to and clear A? in vitro.Our results showed that both cultured astrocytes from AD model mice and LPS-induced cultured astrocytes from WT mice were less capable of removing extracellular A? while HOEC could restore the capacity of aged or injured astrocytes to clear A?.These evidences support the assumption that the function of astrocyte in AD is impaired due to the inflammation occur in brain and anti-inflammatory drugs aimed at restoring astrocyte functions may represent an appropriate approach to treat AD.Therefore,our study raises the role of astrocytes in the AD pathogenesis and the possibility that these cells could be considered a promising target for future AD therapies.