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 the CNS, but distinct physiologic and pathologic roles have not been well defined for this pathway. The capacity to isolate immunochemically human plasma neuron-derived exosomes (NDEs), containing neuron-specific cargo, has permitted characterization of CNS-derived exosomes in living humans. Constituents of the amyloid β-peptide (Aβ)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) and matched cognitively normal controls. ADE levels of β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1), γ-secretase, soluble Aβ42, soluble amyloid precursor protein (sAPP)β, sAPPα, 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 in NDEs from cultured rat type-specific neural cells. Levels of BACE-1 and sAPPβ were significantly higher and of GDNF significantly lower in ADEs of patients with AD than in those of controls, but not significantly different in patients with FTD than in controls. Abundant proteins of the Aβ42 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.-Goetzl, E. J., Mustapic, M., Kapogiannis, D., Eitan, E., Lobach, I. V., Goetzl, L., Schwartz, J. B., Miller, B. L. Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease.

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

“…Plasma exosome cargoes could have prognostic value in AD 158 ; astrocyte-derived exosomes contain higher levels of soluble Aβ 42 and proteins of the Aβ 42 -generating pathway (such as β-secretase 1, γ-secretase, soluble APPβ and soluble APPα) and phosphorylated tau than do neuron-derived exosomes. Levels of β-secretase 1 and soluble APPβ in astrocyte-derived exosomes are higher in patients with AD than in healthy controls 159 .…”

Exosomal biomarkers in Down syndrome and Alzheimer's disease

“…As discussed in this review, toxic Aβ peptides and toxic species of P-Tau, neuroinflammation, and oxidative stress can all alter exosome content, secretion rate, and the cell-to-cell messages they carry. Several reports indicate that exosomes produced under pathological conditions can either confer protection or increased pathology to their target cells (Borland and Vilhardt 2017; Chiarini et al 2017; Goetzl et al 2016; Goetzl et al 2017; Kapogiannis et al 2015; Kouwaki et al 2016; Lee et al 2016; Li et al 2013; Papandreou and Tavernarakis 2017). Further study of these processes will provide new insights into how AD pathology spreads throughout the brain and the role of exosomes in this process.…”

“…Exosomal screening from blood samples allows insights into the profile of proteins secreted from neurons, as well as glial cells in the brain (Goetzl et al 2016), and therefore may offer a “liquid biopsy” of ongoing pathological processes for different CNS cell types. This is particularly useful when working in the DS community where confounds of intellectual disability and functionality make a diagnosis of dementia more difficult.…”

“…Because of this, the cargo carried by CNS-derived exosomes may serve as markers of underlying CNS changes that occur in advance of changes in circulating proteins. Because CNS-derived exosomes have unique surface markers that reflect their cell of origin, targeted examinations of neuron-, astrocyte-, or endothelial cell-derived exosomes can be employed (Fiandaca et al 2015; Kapogiannis et al 2015; Goetzl et al 2016; Goetzl et al 2017). After targeted selection using antibodies directed against the cell-type-specific surface marker(s) for an exosome population of interest, examination of specific exosomal cargos may be used to probe this unique biological niche that may provide a “liquid biopsy snapshot” of current cellular processes.…”

“…These data are fascinating and can potentially lead to a much better understanding of how AD pathology spreads between brain regions, although it is important to highlight that these studies remain in an early stage of inquiry. Astrocyte-derived exosomes from patients with AD have also been purified by Goetzl et al (2016) using glial surface markers (Goetzl et al 2016). They displayed higher levels of both Aβ and p-Tau, as well as the β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) than neuron-derived exosomes from the same samples.…”