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) and at their preclinical stage 3 to 8 yr earlier (AD), with no differences between values at stages AD and AD. 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.

A Brief History of Adherons: The Discovery of Brain Exosomes

“…Finally, essentially all CNS growth factors, such as FGF, NGF, GDNF, and brain-derived neurotrophic factor (BDNF), are small basic proteins that bind HSPG. Thus, they have the potential to be found in exosomes, and this has indeed been seen in several studies [ 46 , 47 , 48 ]. Importantly, exosomes could provide a safe mechanism for transporting these molecules between cells and, if exosomes are incorporated into the ECM, then this would also be a way to keep the growth factors in the vicinity of the cells that secrete them.…”

Brain Derived Exosomes Are a Double-Edged Sword in Alzheimer’s Disease

“…Additionally, lowdensity LRP 6, REST, heat shock factor protein 1, HSP, and AMPA receptor levels are also lower in BDEs from the plasma of AD patients (Goetzl et al, 2015(Goetzl et al, , 2016bWinston et al, 2016). Furthermore, neurexin 2α, GluA4-containing glutamate receptor, and neuroligin 1, essential proteins for long-term potentiation processes, were all significantly reduced in BDEs from the plasma of patients 6−11 years prior to AD diagnosis and, along with neuronal pentraxin 2, were all downregulated in BDEs (Goetzl et al, 2018(Goetzl et al, , 2019. These proteins are all involved in normal homeostasis of neurons.…”

The Function of Astrocyte Mediated Extracellular Vesicles in Central Nervous System Diseases

“…Astrocytes are transformed into A1-type astrocytes which results in neuronal cell death and damages in AD. Neurotrophic factors levels released by astrocyte exosomes were lower at the early stage of AD with no further depletion of neurotropic levels by the progression of the disease in the later stages ( Goetzl et al, 2019 ). The number of complement proteins in plasma astrocyte-derived exosomes are usually irregular in AD and are not the same in mild cognitive impairment ( Winston et al, 2019 ).…”