NFL and pTau species from plasma neuronal and astrocyte exosomes correlate with neuropathological development and neurodegeneration in Down Syndrome

Abstract

AbstractBackgroundIndividuals with Down Syndrome (DS) develop Alzheimer’s disease (AD). Plasma Neurofilament (NFL), phospho tau181, and 231 (pTau181 and 231) are currently considered promising blood‐based biomarkers of brain tau pathology in AD. However, it is still unknown whether the use of exosomal NFL and different pTau epitopes offers overlapping or complementary information about tau pathology information in this population. Using biobanked DSBI plasma samples, we aimed to understand the relationship between blood‐based exosome derived NFL, pTau181 and 231 with age, brain amyloid and tau pathology, APOE status, as well as cognitive and functional performance in non‐demented DS individuals. We hypothesized that the relationship between NFL, pTau‐181, and 231 derived from plasma neuronal and astrocyte exosomes (NDEs/ADEs) with that of other fluid and imaging biomarkers might help to accurately assess brain AD pathology in DS adults.MethodExosomes were isolated from the plasma of adult DS individuals who were enrolled in DSBI. Exosomes were precipitated and isolated using an ExoQuick kit. Isolated exosomes were enriched for NDEs and ADEs using antibodies against neuronal (L1CAM) and astrocyte (GLAST), respectively, followed by magnetic immunocapture and fluorescence‐activated cell sorting. NDEs and ADEs were assessed for their size and marker proteins by Nanosight, electron microscopy, and ELISA. NFL was quantified by SIMOA assays, while pTau epitopes 181 and 231 were quantified by MSD assays in NDEs and ADEs. We compared the diagnostic accuracy of exosomal p‐tau epitopes with NFL levels. We analyzed imaging data and cognitive measures in relation to NFL, pTau181, and pTau231 of NDEs and ADEs in adults with DS.ResultBlood‐based NDEs and ADEs showed expected exosomal size, shape, and distribution. ELISA showed the presence of exosome marker proteins on NDEs and ADEs. The p‐tau epitopes showed correlations with each other. We showed significant correlations of exosomal NFL and pTau epitopes with age, brain amyloid, tau pathology, APOE status, and cognitive and functional performance.ConclusionThe correlations reported here lay a foundation to study the use of plasma‐derived exosomal NFL and pTau181, and pTau231 as a “combination biomarker” in clinical trials and to better understand the neurodegenerative trajectories in DSAD.