Pathological consequences of microglial derived exosome (MDEs) cargo in vivo

Abstract

AbstractBackgroundExosome cargo proteins may serve as useful biomarkers for AD however very few studies have characterized the pathological consequences of exosome cargo in vivo. We determined that neuronally‐derived exosomes isolated from autopsy‐confirmed demented AD patients induced AD‐like neuropathology in the WT mouse CNS. Here, we extended our previous studies to investigate the neuropathological and behavioral consequences of plasma cargo proteins derived from microglia cells in vivo.MethodPlasma exosomes derived from autopsy‐confirmed, cognitively normal controls and demented AD patients were extracted, precipitated, and enriched against a microglial source (TMEM119, MDE) using magnetic immunocapture. MDEs were characterized by Nanosight and exosome marker profiling. MDEs were injected unilaterally into the brains of normal mouse CNS. Brains from MDE injected mice were probed for AD‐related proteins to confirm cargo transfer to recipient cells at 3 and 6 months post injection (mpi). Deficits in spatial learning and memory, gait stability and anxiety were assessed at 6 mpi.ResultPlasma MDEs demonstrate similar size distributions and shape to previously reported exosome preparations. MDEs were positive for exosome marker Flotilin‐1; microglial markers CD68 and IBA1 and negative for astrocyte marker, GLAST. At 3mpi, pathological forms of tau, as measured by PHF1 and MC1, and amyloid beta (Ab) as measured by 6E10, were observed the cortex and hippocampus of MDE injected mouse. At 6 mpi, we will determine the neuropathological behavioral consequence of MDE cargo in vivo.ConclusionMDEs can transfer AD‐related proteins to normal mouse CNS. The behavioral consequence of MDE cargo in vivo is currently being investigated.