Altered levels of plasma neuron‐derived exosomes and their cargo proteins characterize acute and chronic mild traumatic brain injury

Abstract

Neuron‐derived exosomes (NDEs) were enriched by anti‐L1CAM antibody immunoabsorption from plasmas of subjects ages 18–26 yr within 1 wk after a sports‐related mild traumatic brain injury (acute mTBI) (n = 18), 3 mo or longer after the last of 2–4 mTBIs (chronic mTBI) (n = 14) and with no recent history of TBI (controls) (n = 21). Plasma concentrations of NDEs, assessed by counts and levels of extracted exosome marker CD81, were significantly depressed by a mean of 45% in acute mTBI (P < 0.0001), but not chronic mTBI, compared with controls. Mean CD81‐normalized NDE levels of a range of functional brain proteins were significantly abnormal relative to those of controls in acute but not chronic mTBI, including ras‐related small GTPase 10, 73% decrease; annexin VII, 8.8‐fold increase; ubiquitin C‐terminal hydrolase L1, 2.5‐fold increase; AII spectrin fragments, 1.9‐fold increase; claudin‐5, 2.7‐fold increase; sodium‐potassium‐chloride cotransporter‐1, 2.8‐fold increase; aquaporin 4, 8.9‐fold increase (3.6‐fold increase in chronic mTBI); and synaptogyrin‐3, 3.1‐fold increase (1.3‐fold increase in chronic mTBI) (all acute mTBI proteins P < 0.0001). In chronic mTBI, there were elevated CD81‐normalized NDE levels of usually pathologic β‐amyloid peptide 1‐42 (1.6‐fold, P < 0.0001), P‐T181‐tau (2.2‐fold, P < 0.0001), P‐S396‐tau (1.6‐fold, P < 0.01), IL‐6 (16‐fold, P < 0.0001), and prion cellular protein (PRPc) (5.1‐fold, P < 0.0001) with lesser or greater (IL‐6, PRPc) increases in acute mTBI. Increases in NDE levels of most neurofunctional proteins in acute, but not chronic, mTBI, and elevations of most NDE neuropathological proteins in chronic and acute mTBI delineated phase‐specificity. Longitudinal studies of more mTBI subjects may identify biomarkers predictive of and etiologically involved in mTBI‐induced neurodegeneration.—Goetzl, E. J., Elahi, F. M., Mustapic, M., Kapogiannis, D., Pryhoda, M., Gilmore, A., Gorgens, K. A., Davidson, B., Granholm, A.‐C., Ledreux, A. Altered levels of plasma neuron‐derived exosomes and their cargo proteins characterize acute and chronic mild traumatic brain injury. FASEB J. 33, 5082–5088 (2019). http://www.fasebj.org

Traumatic brain injury increases plasma astrocyte‐derived exosome levels of neurotoxic complement proteins

“…As was found in a previous study of extracellular vesicle complement proteins, their levels for the same six subjects in an acute phase of sTBI were significantly higher in ADEs than NDEs (Table ). Plasma levels of NDEs had been shown to be decreased acutely after TBI . In the current study, plasma levels of ADEs determined by counts and CD81 content were significantly lower for the acute sTBI group, but not any of the chronic TBI groups, relative to those of corresponding controls (Table ).…”

“…Plasma levels of NDEs had been shown to be decreased acutely after TBI. 32 In the current study, plasma levels of ADEs determined by counts and CD81 content were significantly lower for the acute sTBI group, but not any of the chronic TBI groups, relative to those of corresponding controls (Table 3). Therefore, all values for ADE complement proteins in Figures 1 and 2 In the acute phase of sTBI, within 1 week of injury, CD81normalized ADE levels of complement proteins C4b, factor D, Bb, and MBL of all three pathways as well as shared effector proteins C3b and C5b-9 TCC were significantly higher than those of controls ( Figure 1).…”

(−)‐Phenserine tartrate (PhenT) as a treatment for traumatic brain injury

“…PhenT’s activation of multiple pathways provides the potential to support neuroprotective and neuro‐reparative mechanisms of relevance to multiple coinciding pathological processes instigated by TBI, which are likely different across human individuals that suffer a TBI event. Furthermore, it may be possible to follow key markers of these pathways in plasma sampled extracellular vesicles enriched for neuronal and astrocytic origin, and evaluate whether they are altered by PhenT treatment. In the light of its prior demonstration of safety in long‐term human studies, PhenT warrants evaluation in human TBI.…”

“…Analysis of the contents of such extracellular vesicles provides a window to the contents of neural cells within the brain in relation to their response to physiological challenges, disease, and its progression and responses to drugs . In this regard, extracellular vesicles are proving increasingly valuable as a source of potential biomarkers to predict TBI outcomes . However, as they are key role players in implementing intercellular communication and initiating physiological responses, the contents of extracellular vesicles can additionally be valuably applied to drug screening.…”

Exosome release and cargo in Down syndrome

“…Then, streptavidin‐Plus Ultralink resin (Thermo Scientific, Inc.) plus BSA is added to the suspension and incubated at room temperature. Immunoabsorbed samples are centrifuged followed by removal of supernatants and each resin pellet suspended in 0.1 M of glycine‐HCl (pH 3.0), incubated and centrifuged according to standard protocols (Goetzl et al, ; ; ; Hamlett, Goetzl, et al, ). Supernatants containing the CNS‐derived exosomes are neutralized with 1 M of Tris–HCl and then lysed with M‐PER lysis buffer.…”