Plasma Small Extracellular Vesicles with Complement Alterations in GRN/C9orf72 and Sporadic Frontotemporal Lobar Degeneration

Abstract

Cutting-edge research suggests endosomal/immune dysregulation in GRN/C9orf72-associated frontotemporal lobar degeneration (FTLD). In this retrospective study, we investigated plasma small extracellular vesicles (sEVs) and complement proteins in 172 subjects (40 Sporadic FTLD, 40 Intermediate/Pathological C9orf72 expansion carriers, and 49 Heterozygous/Homozygous GRN mutation carriers, 43 controls). Plasma sEVs (concentration, size) were analyzed by nanoparticle tracking analysis; plasma and sEVs C1q, C4, C3 proteins were quantified by multiplex assay. We demonstrated that genetic/sporadic FTLD share lower sEV concentrations and higher sEV sizes. The diagnostic performance of the two most predictive variables (sEV concentration/size ratio) was high (AUC = 0.91, sensitivity 85.3%, specificity 81.4%). C1q, C4, and C3 cargo per sEV is increased in genetic and sporadic FTLD. C4 (cargo per sEV, total sEV concentration) is increased in Sporadic FTLD and reduced in GRN+ Homozygous, suggesting its specific unbalance compared with Heterozygous cases. C3 plasma level was increased in genetic vs. sporadic FTLD. Looking at complement protein compartmentalization, in control subjects, the C3 and C4 sEV concentrations were roughly half that in respect to those measured in plasma; interestingly, this compartmentalization was altered in different ways in patients. These results suggest sEVs and complement proteins as potential therapeutic targets to mitigate neurodegeneration in FTLD.

Free complement and complement containing extracellular vesicles as potential biomarkers for neuroinflammatory and neurodegenerative disorders

“…Compared to HC, C3 EV:plasma ratios were elevated in sporadic FTLD while C4 EV:plasma ratios were decreased in homozygous GRN+ FTLD (136). Moreover, C4 EV:plasma ratios were increased in sporadic FTLD versus GRN+ genetic FTLD but decreased in homozygous GRN+ FTLD versus all other FLTD groups (136).…”

“…Moreover, C4 EV:plasma ratios were increased in sporadic FTLD versus GRN+ genetic FTLD but decreased in homozygous GRN+ FTLD versus all other FLTD groups (136). For C1q, no differences in EV:plasma ratios could be detected amongst all groups investigated (136).…”

“…extracellular vesicles (EVs), astrocyte-EV (AEV), neuronal-EV (NEV), microglial-EV (MEV), not described (ND), not applicable (NA), idiopathic intracranial hypertension (IIH); multiple sclerosis (MS), relapsing-remitting MS, progressive MS (pMS), Alzheimer's disease (AD), Fronto-Temporal Lobar Degeneration (FTLD), Parkinson's disease (PD), Glioblastoma multiforme (GBM), meningioma (MEN), ischemic stroke (IS), subcortical (SC), cortical-subcortical (CSC), mild cognitive impairment (MCI), MCI stable (MCIS), MCI converting to dementia (MCIC), Hoehn and Yahr (HY), healthy controls (HC), age-gender matched healthy controls (A/G HC), homozygous (hom), heterozygous (het), Nanoparticle Tracking Analysis (NTA), Bicinchoninic Acid Assay (BCA) Bradford assay (BA), mass spectrometry (MS), differential ultracentrifugation (DUC), ultracentrifugation (UC), Annexin A5 (ANXA5), flow cytometry (FC), transmission electron microscopy (TEM), size exclusion chromatography (SEC), high sensitivity flow cytometry (hsFC), immunoprecipitation (IP), Tunable Resistive Pulse Sensing (TRPS), factor H (fH), factor B (fB), factor D (fD), terminal complement complex (TCC), human serum albumin (HSA), heat-shock protein (HSP), A-beta oligomers (AbO), choroid plexus epithelial cells (CPE), wildtype (WT). (136). Additionally, EV-complement related differences between different subgroups of FTLD were also detected.…”

“…Additionally, EV-complement related differences between different subgroups of FTLD were also detected. For example, C4 cargo was decreased in GRN+ homozygous genetic FTLD versus heterozygous GRN+ and pathological C9orf72 genetic FTLD, while EV-associated C4 increased in sporadic FTLD compared to heterozygous GRN+ FTLD (136). C1q, C3 and C4 EV:plasma ratios were also compared between the different groups.…”

microRNA-based predictor for diagnosis of frontotemporal dementia

“…Brain imaging and several biofluid proteins have been proposed as biomarkers for both ALS and FTD (Al Shweiki et al , 2019; Ashton et al , 2021; Bellini et al , 2022; Benussi et al , 2019; Bian et al , 2008; Borroni et al , 2015; Bourbouli et al , 2017; Bright et al , 2019; Chouliaras et al , 2022; Das et al , 2022; Delaby et al , 2020; Eratne et al , 2022; Feneberg et al , 2018; Forgrave et al , 2019; Goncalves et al , 2017; Gonzalez-Garza et al , 2018; Hansson et al , 2019; Hu et al , 2013; Jiskoot et al , 2019; Katisko et al , 2021; Katisko et al , 2020; Krishnan et al , 2022; McCarthy et al , 2018; Meeter et al , 2017; Meeter et al , 2018; Niikado et al , 2019; Oeckl et al , 2022; Prado et al , 2018; Rossi et al , 2018; Sheikh-Bahaei et al , 2017; Silva-Spinola et al , 2022; Teunissen et al , 2016; Thijssen et al , 2022; Turner et al , 2009; van der Ende et al , 2020; Verde et al , 2021; Wilson et al , 2022; Xu et al , 2016). Among the proteins, noticeable are neurofilament light chain (NfL), TDP-43 and, phospho-tau, amyloid beta and glial fibrillary acidic protein (GFAP).…”