Improvement of neuronal cell survival by astrocyte‐derived exosomes under hypoxic and ischemic conditions depends on prion protein

Abstract

Prion protein (PrP) protects neural cells against oxidative stress, hypoxia, ischemia, and hypoglycemia. In the present study we confirm that cultured PrP-deficient neurons are more sensitive to oxidative stress than wild-type neurons and present the novel findings that wild-type, but not PrP-deficient astrocytes protect wild-type cerebellar neurons against oxidative stress and that exosomes released from stressed wild-type, but not from stressed PrP-deficient astrocytes reduce neuronal cell death induced by oxidative stress. We show that neuroprotection by exosomes of stressed astrocytes depends on exosomal PrP but not on neuronal PrP and that astrocyte-derived exosomal PrP enters into neurons, suggesting neuronal uptake of astrocyte-derived exosomes. Upon exposure of wild-type astrocytes to hypoxic or ischemic conditions PrP levels in exosomes were increased. By mass spectrometry and Western blot analysis, we detected increased levels of 37/67 kDa laminin receptor, apolipoprotein E and the ribosomal proteins S3 and P0, and decreased levels of clusterin/apolipoprotein J in exosomes from wild-type astrocytes exposed to oxygen/glucose deprivation relative to exosomes from astrocytes maintained under normoxic conditions. The levels of these proteins were not altered in exosomes from stressed PrP-deficient astrocytes relative to unstressed PrP-deficient astrocytes. These results indicate that PrP in astrocytes is a sensor for oxidative stress and mediates beneficial cellular responses, e.g. release of exosomes carrying PrP and other molecules, resulting in improved survival of neurons under hypoxic and ischemic conditions.

Neuroimmune Response in Ischemic Preconditioning

“…One potential mechanism of astrocyte-mediated neuroprotection after IPC may involve limiting neuronal excitotoxicity by clearing glutamate [21], and in stroke astrocytes may protect neurons from oxidative stress [103]. Astrocytes are capable of engaging in spatial buffering, which allows them to transport and metabolize amino acids and glucose, as well as upregulate antioxidants and free radical scavengers in the ischemic region [103,107,[114][115][116]. Prion protein protects neurons against oxidative stress, hypoxia, ischemia, and hypoglycemia, and may be supplied to neurons by astrocytes under ischemic or hypoxic conditions [117].…”

Stimulus‐dependent modifications in astrocyte‐derived extracellular vesicle cargo regulate neuronal excitability

“…EVs are constitutively released from most (if not all) cells, and EV shedding can be induced by a variety of stimuli. There is an increasing amount of evidence that EVs, particularly ADEVs, can regulate neurological function (Chaudhuri et al, ; Guitart et al, ; Hu et al, ; Xin et al, ), and recent findings suggest that ADEVs communicate to the peripheral immune system (Dickens et al, ). Although it has been suggested that EV cargo is modified by the stimulus used to induce release, we are only aware of one study (Drago et al, ) that has compared the cargo of EVs released in response to a stimulus (ATP) to constitutive release.…”

Fibroblast Growth Factor 2‐Mediated Regulation of Neuronal Exosome Release Depends on VAMP3/Cellubrevin in Hippocampal Neurons

“…In the injured CNS, EVs were recently found to cross the blood–brain barrier and promote neuroinflammation . Furthermore, certain types of EVs appear to support neuronal survival under conditions of ischemic stress . In neurodegenerative diseases, EVs contribute to the seeding and spreading of toxic protein aggregates, and influence the aggregation process and clearance of these aggregates …”