Associations of cerebrospinal fluid amyloidogenic nanoplaques with cytokines in Alzheimer’s disease

Background:The aggregation of amyloidβ(Aβ)is central in the pathogenesis of Alzheimer’s disease(AD).Recently it has been shown that specifically,larger,Thioflavin T-binding Aβaggregates are associated with increased neuroinflammation and cytokine release.This study was aimed to quantify fibrillary amyloid aggregates,so-called nanoplaques,and investigate their relationship with cytokines in the cerebrospinal fluid(CSF).Methods:CSF was collected from 111 patients assessed for cognitive complaints at the Oslo University Hospital Memory Clinic.The patients were grouped based on their amyloid status.The CSF nanoplaque concentration was quantified with the Thioflavin T-fluorescence correlation spectroscopy(ThT-FCS)assay.The levels of nine cytokines(eotaxin-1,granulocyte stimulating factor,interleukin[IL]-6,IL-7,IL-8,monocyte chemoattractant protein-1,gammainduced protein 10,macrophage inflammatory protein[MIP]-1α,and MIP-1β)were quantified with a magnetic bead-based multiplex assay and read on a Luminex IS 200 instrument.Results:There were 49 amyloid-negative and 62 amyloid-positive patients in the cohort;none of the cytokines differed significantly between the amyloid groups.The increased nanoplaque levels were associated with levels of MIP-1βbelow the lower limit of quantification,and with decreased levels of MIP-1αand IL-8.The associations remained significant when adjusted for age,sex,cognitive function,apolipoproteinε4 status and CSF core biomarker levels.Conclusion:The cytokine levels were not associated with amyloid status in this cohort.The nanoplaque levels were negatively associated with MIP-1β,MIP-1αand IL-8,which is in line with recent findings suggesting that the upregulation of some cytokine markers has a protective role and is negatively associated with AD progression.

Effect of Cuzhi liquid on learning and memory dysfunction in a mouse model of Alzheimer's disease

OBJECTIVE: To examine the effects of Cuzhi liquid on learning and memory abilities in a mouse model of Alzheimer's disease(AD).METHODS: One hundred mice were divided into the normal, AD model, piracetam group, Cuzhi liquid low dose and Cuzhi liquid high dose, each group 20 mice. The AD mouse model was induced by daily intraperitoneal injection of D-galactose and sodium nitrite. AD mice then received intragastric administration of piracetam or Cuzhi liquid for60 d, and changes in learning and memory abilities were assessed using the water maze test. The activity of acetylcholinsterase(AchE) and monamine oxidase(MAO), and the levels of nitrogen monoxidum(NO) and malonaldehyde(MDA), were measured in brain tissues. Amyloid protein deposition was assessed by methyl violet staining, and B-cell lymphoma-2(Bcl-2) expression in the hippocampal cornus ammonis 1 region was detected by immunohistochemistry.RESULTS: In the water maze test, the escape latency of the model group was longer than that of the normal group(P < 0.01). The escape latency of the three using drug treatment groups was significantly less than that of the normal group(P < 0.05). The activity of AchE and MAO, and the levels of NO and MDA, in the brain of the model group were significantly higher than that of the normal group(P <0.01), but significantly reduced in the three drug treatment groups compared with the model group(P < 0.05). AchE activity showed a greater reduction in the two Cuzhi liquid groups compared with the piracetam group(P < 0.01), to levels similar to the normal group. There were no differences in MAO activity or NO levels between the three drug treatment groups, while MDA levels were reduced more in the high-dose Cuzhi liquid group compared with the other treatment groups(P < 0.01). Hippocampal Bcl-2 expression was significantly reduced in the model group compared with the normal group(P < 0.01), but significantly improved in the three drug treatment groups(P < 0.05). The high-dose Cuzhi liquid group showed a significantly greater recovery in Bcl-2 expression compared with the other treatment groups.CONCLUSION: Cuzhi liquid can improve learning and memory impairment in an AD mouse model.The mechanism of action may relate to reduced AchE and MAO activity, and reduced NO and MDA levels, in the brain, and improved Bcl-2 expression,an inhibitor of apoptosis.