Deficient neurotrophic factors of CSPG4‐type neural cell exosomes in Alzheimer disease

ABSTRACT Exosomes derived from chondroitin sulfate proteoglycan (CSPG) 4 type neural precursor cells (CSPG4Es) were purified from human plasma by sequential immunoabsorption with anti‐CSPG4 and anti‐platelet growth factor receptor α mAb to characterize the potential in vivo roles of CSPG4 cells in neuronal repair. Hepatocyte growth factor, fibroblast growth factors (FGFs)‐2 and ‐13, and type 1 insulin‐like growth factor (IGF‐1), which enhance neuronal survival and functions, were quantified in CSPG4E extracts. For CSPG4Es of 24 healthy control subjects, mean levels of hepatocyte growth factor, FGF‐13, and IGF‐1, but not FGF‐2, were significantly higher by up to 7‐fold than in their neuronal‐derived exosomes, and mean levels of all 4 growth factors were significantly higher by up to 8‐fold than in their astrocyte‐derived exosomes. Mean CSPG4E levels of all growth factors were significantly lower in patients with mild Alzheimer disease (AD) ( n = 24) than in age‐ and sex‐matched cognitively normal control subjects ( n = 24). Mean CSPG4E levels of all growth factors were also significantly lower in 15 patients at the stage of moderate dementia from AD (AD 2 ) and at their preclinical stage 3 to 8 yr earlier (AD 1 ), with no differences between values at stages AD 1 and AD 2 . Current findings suggest that CSPG4 cells export in exosomes higher levels of neurotrophic factors than neurons or astrocytes and that CSPG4E neurotrophic factors are diminished early in AD, with no significant progression of decreases later in the course.—Goetzl, E. J., Nogueras‐Ortiz, C., Mustapic, M., Mullins, R. J., Abner, E. L., Schwartz, J. B., Kapogiannis, D. Deficient neurotrophic factors of CSPG4‐type neural cell exosomes in Alzheimer disease. FASEB J. 33, 231–238 (2019). www.fasebj.org