Apolipoprotein C-III is an Amyloid-β-Binding Protein and an Early Marker for Alzheimer's Disease

Abstract

It has been demonstrated that peripheral injection of anti-amyloid-β (Aβ) antibodies to patients with Alzheimer's disease (AD) and AD transgenic mice facilitate Aβ clearance. We hypothesized that peripheral circulating Aβ-binding proteins also possess the ability to enhance Aβ clearance and the levels of circulating Aβ-binding proteins could serve as early AD biomarkers. Circulating Aβ-binding proteins were isolated from plasma and identified by LC-MS/MS. Their levels were compared among non-demented individuals without AD family history (ND), with AD family history (ND-FH), and patients with mild AD. The results showed that most of the identified Aβ-binding proteins were apolipoproteins, i.e., apoA-I, apoB-100, apoC-III, and apoE. Aβ bound preferentially to apoA-I-enriched HDL, followed by apoC-III- and apoE-enriched VLDL, and bound less favorably to apoB-100-enriched LDL. Levels of apoA-I were reduced in AD patients and could be used to discriminate AD from ND groups (AUC: 0.93); whereas levels of apoC-III were reduced in both ND-FH and AD groups and could be used to differentiate ND-FH from ND individuals (AUC: 0.81). Both the levels of apoA-1 and apoC-III positively correlated with CASI and MMSE scores. In conclusion, these results suggest that plasma apoA-I could be a sensitive AD biomarker and individuals with low plasma levels of apoC-III are at risk for AD.

A core transcriptional signature of human microglia: Derivation and utility in describing region‐dependent alterations associated with Alzheimer's disease

“…The MAG list was enriched in genes from various pathways associated with innate immune signaling, consistent with the inflammatory environment within Alzheimer's brain tissue and the reactivity of microglia within this environment, for example TSPO (Kumar et al, ). It was particularly interesting to note that genes involved in lipid regulation and wound healing, associated with Alzheimer's disease, were over‐represented in the MAGs set (Cervantes et al, ; Lorenzl et al, ; Petit‐Turcotte et al, ; Shih et al, ). Members of the APOC gene family and ECHDC3 are known to regulate levels of certain lipids, linked with Alzheimer's progression (Adunsky et al, ; Desikan et al, ; Lane & Farlow, ).…”

Relation between plasma and brain lipids

“…In Alzheimer's disease mice, Apoa4 deficiency increases amyloid-b load, enhances neuronal loss, accelerates cognitive dysfunction, and increases mortality [92]. Lastly, apoC-III has recently been reported to be associated with amyloid-b levels in the periphery and is of possible interest for use as an early biomarker for Alzheimer's disease [93].…”

Amyloid-Forming Properties of Human Apolipoproteins: Sequence Analyses and Structural Insights

“…Human apoC-III can also form amyloid fibrils in vitro (de Messieres et al 2014). Moreover, apolipoproteins such as apoC-III, apoA-I and apoE were implicated in binding amyloid-β (Aβ) peptide in circulation and were proposed as potential bio-markers or risk factors of Alzheimer’s disease (Lewis et al 2010; Shih et al 2014). …”