Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease

Abstract

Efficient intercellular transfer of RNAs, proteins, and lipids as protected exosomal cargo has been demonstrated in theCNS, but distinct physiologic and pathologic roles have not beenwell definedfor this pathway. The capacity to isolate immunochemically human plasma neuron-derived exosomes (NDEs), containing neuronspecific cargo, has permitted characterization of CNS-derived exosomes in living humans. Constituents of the amyloid b-peptide (Ab)42-generating system now are examined in 2 distinct sets of human neural cells by quantification in astrocyte-derived exosomes (ADEs) and NDEs, enriched separately from plasmas of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD) andmatched cognitively normal controls.ADE levels of b-site amyloid precursor protein-cleaving enzyme 1 (BACE-1), g-secretase, soluble Ab42, soluble amyloid precursor protein (sAPP)b, sAPPa, glial-derived neurotrophic factor (GDNF), P-T181-Tau, and P-S396-Tau were significantly (3-to 20-fold) higher than levels in NDEs for patients and controls. BACE-1 levels also were a mean of 7-fold higher in ADEs than inNDEs fromcultured rat type-specific neural cells. Levels of BACE-1 and sAPPb were significantly higher and ofGDNF significantly lower inADEs of patientswithADthan in those of controls, but not significantly different in patients with FTD than in controls. Abundant proteins of the Ab42 peptide-generating system in ADEs may sustain levels in neurons. ADE cargo proteins may be useful for studies of mechanisms of cellular interactions and effects of BACE-1 inhibitors in AD.