Abstract
Possible involvement of complement (C) systems in the pathogenesis of traumatic brain injury (TBI) was investigated by quantifying Cproteins in plasma astrocyte-derived exosomes (ADEs) of subjects with sports-related TBI (sTBI) and TBI in military veterans (mtTBI) without cognitive impairment. All sTBI subjects (n=24) had mild injuries, whereas eight of the mtTBI subjects had moderate, and 17 had mild injuries. Plasma levels of ADEs were decreased after acute sTBI and returned to normal within months. Cprotein levels in ADEs were from 12- to 35-fold higher than the corresponding levels in neuron-derived exosomes. CD81 exosome marker-normalized ADE levels of classical pathway C4b, alternative pathway factor D and Bb, lectin pathway mannose-binding lectin (MBL), and shared neurotoxic effectors C3b and C5b-9 terminal C complex were significantly higher and those of C regulatory proteins CR1 and CD59 were lower in the first week of acute sTBI (n=12) than in controls (n=12). Most C abnormalities were no longer detected in chronic sTBI at 3-12 months after acute sTBI, except for elevated levels of factor D, Bb, and MBL. In contrast, significant elevations of ADE levels of C4b, factor D, Bb, MBL, C3b and C5b-9 terminal C complex, and depressions of CR1 and CD59 relative to those of controls were observed after 1-4 years in early chronic mtTBI (n=10) and persisted for decades except for normalization of Bb, MBL, and CD59 in late chronic mtTBI (n=15). Complement inhibitors may be useful therapeutically in acute TBI and post-concussion syndrome.
Highlights
Astrocytes are abundant glial cells in the human central nervous system (CNS) that normally support neurons through promotion of development, nutrition, survival, dendrite outgrowth, and synapse formation [1,2,3]
Plasma levels of astrocyte-derived exosomes (ADEs) determined by counts and CD81 content were significantly lower for the acute sports-related TBI (sTBI) group, but not any of the chronic TBI groups, relative to those of corresponding controls (Table 3)
The elevated ADE levels of complement component C4b of the classical pathway and factors D and Bb of the alternative pathway in acute sTBI relative to controls resemble in magnitude those observed in Alzheimer’s disease (Fig. 1) [18, 19]
Summary
Astrocytes are abundant glial cells in the human central nervous system (CNS) that normally support neurons through promotion of development, nutrition, survival, dendrite outgrowth, and synapse formation [1,2,3]. ADE content of the complement-regulatory membrane proteins CD59, CD46, decay-accelerating factor, and complement receptor type 1 (CR1), but not of fluid-phase factor I, were significantly lower in AD than controls [18]. These data suggested a neurotoxic opsonic role for C3b and the possibility of direct neuronal membrane attack by C5b-9 terminal complement complex (TCC) in AD. Such complement abnormalities were detected in the phase of mild cognitive impairment several years preceding dementia and in clinically-evident mild AD, but not in preclinical AD 512 years before memory loss [18, 19]
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