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

Abstract

Background The aggregation of amyloid β (Aβ) is central in the pathogenesis of Alzheimer’s disease (AD). Recently it has been shown that specifically, larger, Thioflavin T-binding Aβ aggregates 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, gamma-induced 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-1β below the lower limit of quantification, and with decreased levels of MIP-1α and IL-8. The associations remained significant when adjusted for age, sex, cognitive function, apolipoprotein ε4 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-1α and 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.

Serum Amyloidogenic Nanoplaques and Cytokines in Alzheimer’s Disease: Pilot Study in a Small Naturalistic Memory Clinic Cohort

“…Cytokine and nanoplaque levels were not associated in serum, in contrast to previous findings in CSF in a different patient cohort [ 14 ]. This suggests that while CSF nanoplaques appear to be associated with markers of neuroinflammation, serum nanoplaques are not good indicators of cytokine-driven systemic inflammatory or anti-inflammatory activity.…”

“…Most notably, the cohort is small to begin with (49 patients), and a major caveat in the interpretation of our data is that we only have complete biomarker profiles for a small subgroup (26 patients). However, in our previous research on the NorCog population we have found very high congruence between clinical- and biomarker-based classification of patients [ 14 ]. Furthermore, we do not have paired measurements of nanoplaque levels in CSF and serum from the same patient, and we cannot be certain of the composition of the quantified nanoplaques, which limits our interpretations as previously discussed.…”

“…In our cohort, serum IL-8 and G-CSF levels were increased in patients with clinical AD compared to non-AD patients. In the CSF, IL-8 levels are negatively associated with amyloidogenic nanoplaques [ 14 ]; it is unclear why the relationship between IL-8 and nanoplaques is not paralleled in serum. One potential explanation is that CSF IL-8 levels are higher than serum IL-8 levels in AD, suggesting that cytokines in the CSF are derived from the brain and not the periphery [ 30 ].…”

“…However, we have previously shown that ThT-labelled amyloidogenic aggregates composed of > 40 monomers with a cross-β sheet structure, hereby called nanoplaques, can be quantified in serum [ 11 ] and CSF [ 12 ] by a ThT fluorescence correlation spectroscopy (ThT-FCS) assay. Moreover, nanoplaques in CSF are increased in AD [ 13 ] and associated with several cytokines [ 14 ].…”

“…Similarly, patients with AD have increased levels of serum nanoplaques compared to healthy controls [ 11 ]. However, it is not known whether the association between nanoplaques and cytokines that has been observed in the CSF [ 14 ], extends to serum.…”