New Evidence Linking Clusterin and Other Complement Proteins to Alzheimer’s Progression and Prediction

Clusterin Complement Proteins Alzheimer’s
Clusterin Complement Proteins – Alzheimer’s

A study recently published in the Journal of Alzheimer’s Disease gives hope in the search of Alzheimer’s disease (AD) biomarkers indicating that some complement factors such as clusterin may serve as reliable predictors of Alzheimer’s disease progression.

The current lack of plasma biomarkers for diagnosis, stratification or prediction of outcome in AD is a major deficit that compromises early diagnosis and informed therapeutic choice. A handful of plasma markers have been described but are untested in preclinical disease and likely unsuitable for early diagnosis.

The recognition that inflammation is an important player in Alzheimer’s disease and likely an early event in disease pathogenesis brings to the fore the potential use of markers of inflammation. Nonspecific indicators of peripheral inflammation such as Creactive protein and inflammatory cytokines have proved unreliable as markers of disease or disease progression, suggesting that a more targeted approach, focussing on specific inflammatory pathways might be more rewarding.

It is well known that inflammation and pro-inflammatory mediators contribute to the pathogenesis of dementia and Alzheimer’s. The complement system, part of the innate immunity and a potent driver of inflammation, “enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells”.

Previous research also implicates this innate immune system in the development of Alzheimer’s disease. Several published studies have explored whether plasma levels of complement components, regulators or activation products are altered in AD or predict progression in the disease. In one of the first untargeted proteomics analyses of plasma in AD, complement factor H (FH) was found to be elevated in AD plasma compared to controls.

In the Journal of Alzheimer’s Disease study, Svetlana Hakobyan and colleagues from Cardiff University, King’s College London and University of Oxford, UK, used a custommade tenanalyte multiplex set on the MSD platform to measure selected candidate AD biomarker complement proteins and activation products. The set comprised FH (measured as the individual Y402 and H402 alleles [22]), clusterin, FI, C1s, C9, C4d, Bb, iC3b, TCC. The four complement activation products selected for measurement included markers of classical (C4d, iC3b), alternative (Bb, iC3b) and terminal
(terminal complement complex; TCC) pathway

The authors compared samples from individuals with Alzheimer’s and healthy matched controls. The authors also studied samples from individuals with mild cognitive impairment (MCI) who had subsequently converted to dementia, when re-assessed 12 months later (convertors), or who had remained stable over the period of assessment (non-convertors). The researchers also designed a multiplex assay to measure simultaneously ten complement analytes.

The investigators demonstrated that clusterin alone among the analytes tested differentiated AD patients from matched controls, while clusterin, FI and TCC were all significantly different between MCI convertors and nonconvertors at one year postsampling. In the sample set authors used, 26% of the MCI cases progressed to dementia at one year; this is markedly higher than published annual conversion rates, typically around 10%, although considerable variation between sample sets has been noted.

Association of plasma clusterin levels with rate of cognitive decline has been reported both in MCI and AD in each of these studies, higher clusterin levels predicted more rapid decline. The results reported in this study demonstrating substantially higher plasma clusterin in MCI convertors compared to nonconvertors robustly support these findings and show that elevated plasma clusterin is a powerful predictor of progression.

The study provides further evidence that complement proteins may contribute to disease progression in Alzheimer’s, and that combinations of complement biomarkers can aid diagnosis, patient stratification and prediction of outcome in MCI and Alzheimer’s disease.

Professor Paul Morgan, the senior author of the study, and director of Cardiff University’s Systems Immunity Research Institute, stated “We hope to build on this in order to develop a simple blood test that can predict the likelihood of developing Alzheimer’s disease in older people with mild, and possibly innocent, memory impairment.”

Source: J Alzheimers Dis. 2016 Sep 6;54(2):707-16. doi: 10.3233/JAD-160420.

Cover Image Credit (Left panel): Primary structure of secreted clusterin. Secreted CLU is composed of two polypeptide chains connected by five disulfide bonds, derived from an intracellular precursor. In the first processing step, the 22-mer secretory signal peptide is cleaved from the 449-amino acid precursor. Subsequently the chain is cleaved again between Arg227-Ser228 to generate an a-chain and a b-chain. These are assembled in antiparallel fashion to generate a heterodimeric molecule in which the cysteine-rich centers (red boxes) are linked by five disulfide bridges (black lines). The mature protein is 17–27% N-linked carbohydrate by mass. The three sites for N-linked glycosylation on each chain are clustered around a central region of ordered structure stabilized by the disulfide bonds forming a core that is hydrophilic due to the glycosyl groups. The six sites for N-linked glycosylation are indicated (white ellipses). Five predicted amphipathic a-helices (yellow ovals) in the otherwise disordered arms may be important for binding to hydrophobic regions exposed on misfolded proteins and for insertion into lipid structures. Amino acid numbering for the N- and C-termini, the cleavage sites, and the six sites for N-linked glycosylation (white ovals) are indicated. (From (56) with permission from the publisher, order number 501613529). From: Therapeutic Potential of the Molecular Chaperone and Matrix Metalloproteinase Inhibitor Clusterin for Dry Eye by M. Elizabeth Fini et al. Int. J. Mol. Sci. 2021, 22(1), 116.