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Complement Protein Levels in Plasma Astrocyte-Derived Exosomes Are Abnormal in Conversion From Mild Cognitive Impairment to Alzheimer's Disease Dementia

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Complement Protein Levels in Plasma Astrocyte-Derived Exosomes Are Abnormal in Conversion From Mild Cognitive Impairment to Alzheimer's Disease Dementia

Charisse N Winston et al. Alzheimers Dement (Amst).

Abstract

Introduction: Levels of complement proteins (CPs) in plasma astrocyte-derived exosomes (ADEs) that are abnormal in Alzheimer's disease (AD) have not been assessed in mild cognitive impairment (MCI).

Methods: Participants (n = 20 per group) had either MCI converting to dementia within 3 years (MCIC), MCI remaining stable over 3 years (MCIS), Alzheimer's disease, or were controls. CPs of ADEs isolated from plasmas by anti-human glutamine aspartate transporter antibody absorption were quantified by ELISAs.

Results: ADE levels of C1q and C4b of the classical pathway, factor D and fragment Bb of the alternative pathway, and C5b, C3b, and C5b-C9 of both pathways were significantly higher in patients with MCIC than those with MCIS. ADE levels of inhibitory CPs decay-accelerating factor, CD46, CD59, and type 1 complement receptor were significantly lower in patients with MCIC than those with MCIS.

Discussion: ADE CPs are components of neurotoxic neuroinflammation that may be predictive biomarkers of MCI conversion to Alzheimer's disease.

Keywords: Biomarkers; Cognitive loss; Complement regulators; Neurodegeneration; Neuroinflammation.

Figures

Fig. 1
Fig. 1
ADE levels of complement effector proteins in cross-sectional control, MCI, and AD groups. Each point represents the value for a control or patient, and the horizontal line in point clusters is the mean level for that group. Mean ± SEM for control, stable MCI (MCIS), MCI that converted to dementia (MCIC), and AD patient values, respectively, are 14,560 ± 1423, 8845 ± 744, 51,274 ± 3706, and 46,135 ± 3001 pg/mL for C1q; 66,936 ± 5660, 98,464 ± 13,248, 698,662 ± 57,983, and 162,747 ± 8076 pg/mL for C4b; 1478 ± 171, 1539 ± 200, 5763 ± 653, and 5875 ± 816 pg/mL for factor D; 106,508 ± 13,449, 22,503 ± 2908,144,103 ± 13,792, and 245,094 ± 15,609 pg/mL for factor B fragment Bb; 3105 ± 198, 3109 ± 319, 5937 ± 478, and 5238 ± 244 pg/mL for C5b; 25,571 ± 2412, 7453 ± 876, 64,389 ± 4593, and 78,256 + 5499 pg/mL for C3b; 358 ± 35.0, 523 ± 47.2, 1117 ± 117, and 1187 ± 134 pg/mL for C5b-C9 TCC; and 1130 ± 131, 1122 ± 110, 1123 + 116, and 1157 ± 134 pg/mL for MBL. The significance of differences between values for controls and AD patients, and between values for MCIS and MCIC patients, was calculated by an unpaired Student's t-test and shown over the last two bars of each set; * = P < .01 and ** = P < .0001. Abbreviations: ADE, astrocyte-derived exosome; AD, Alzheimer's disease; MCI, mild cognitive impairment; MBL, mannose-binding lectin.
Fig. 2
Fig. 2
ADE levels of complement regulatory proteins in cross-sectional control, MCI, and AD groups. Each point represents the value for a control or patient, and the horizontal line in point clusters is the mean level for that group. Mean ± SEM for control, MCIS, MCIC, and AD patient values, respectively, are 35,166 ± 3981, 11,486 ± 1581, 2796 ± 230, and 3825 ± 499 pg/mL for DAF; 62.4 ± 5.48, 245 ± 37.3, 47.1 ± 4.78, and 35.3 ± 2.91 pg/mL for CD46; 473 ± 38.2, 475 ± 51.9, 268 ± 29.9, and 286 ± 20.6 pg/mL for CR1; and 1268 ± 84.1, 865 ± 103, 584 ± 60.6, and 353 ± 38.5 pg/mL for CD59. The significance of differences between values for controls and AD patients, and between values for MCIS and MCIC patients, was calculated by an unpaired Student's t-test and shown over the last two bars of each set; + = P < .05, * = P < .01, and ** = P < .0001. Abbreviations: ADE, astrocyte-derived exosome; AD, Alzheimer's disease; MCI, mild cognitive impairment; MCIC, MCI that converted to dementia; MCIS; stable MCI.

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