As already mentioned in Focus on Clusterin! - part one, clusterin is able to form complexes with immunoglobulins, components, paraoxonase, leptin, lipids, heparin, bacteria, complement and others. It can also bind to beta amyloid and inhibit formation of its fibrils.
Clusterin has been connected to a plethora of functions such as phagocyte recruitment, reduced aggregation of serum proteins, prevention of complement attack, apoptosis inhibition, membrane remodeling, lipid transport, hormone transport, matrix metalloproteinase inhibition and reduction of oxidative stress.
Clusterin and Alzheimer’s Disease
An Old Molecule with a New Role. The age-dependent decline of chaperones-assisted mechanisms is thought to contribute to proteostasis diseases, including amyloidosis. Clusterin is a as chaperone implicated here in the processing of misfolded and aggregated extracellular proteins.
The mechanism involves a preferential binding to the hydrophobic patches exposed on early oligomeric assemblies, regardless of their identity.
Significant clinical implication is its interaction with beta amyloid Aβ1-40 oligomer, providing a significant link between clusterin and Alzheimer's disease. The binding of clusterin may prevent Aβ oligomers associated toxicity.
The results of studies by Jian-Fang and his group suggest that infusion of clusterin peptide offers a promising therapeutic approach to reduce Aβ deposition as well as cerebral amyloid angiopathy (CAA).
It is unclear now whether the predominant effect is mediated by their proteolysis and/or rendering oligomers less toxic by shielding of their hydrophobic patches thus inhibiting their growth.
Clusterin and oxidative stress in ageing
Oxidative stress in ageing and age-related diseases
CLU has been involved in various physiological processes and in many pathophysiological disturbances related to ageing, cancer progression, diabetes, vascular damage, neuron or kidney degeneration.
Although these diseases are unrelated in their etiology or clinical presentation, these represent states of elevated oxidative stress, which can promote damage-related aggregation of target proteins, increase in both genomic instability and programmed cellular death.
Among the properties attributed to CLU so far are its small heat shock protein-like chaperone activity and its involvement in programmed cell death regulation, which are both directly correlated to the main features of oxidant injury.
The presence of both a heat shock transcription factor-1 and an activator protein-1 element in the clusterin gene promoter indicate that clusterin itself can be a very efficient and sensitive biosensor to reactive oxygen species.
Conclusions
Although clusterin can play a significant role in various physiological and pathological states from a diagnostic perspective it cannot be attributed to a specific condition. This diminishes its primary diagnostic power and shifts it to the role of supportive marker.
Its diiagnostic strength is in combination with other markers which can enable fine grading or more relevant description of diagnosed conditions, determining possible resistances to chemotherapy or aggressiveness of tumor cells, or degree of systemic inflamation or oxidative stress.
Therefore the level of clusterin can in certain circumstances refer to initial stress conditions.
Therapeutically
There is therapeutic potential of clusterin isoforms in clinical practice where there is a need to
- stimulate pathways influencing sCLU/nCLU balance
- direct supplementation of recombinant sClu in order to replace age or stress related decline
- or mimicking its function to reduce nonphysiological/ pathological stress
The pathway leading to functional biological treatment can be quite long and tricky because of high glycosylation and multimeric behavior of sClu and because of uncertainties connected to the many functions of clusterin under various pathophysiological conditions.
But it can be envisioned that Clusterin based therapy could be successful for metabolic disorders, oxidative stress and potentially with Alzheimer disease.
New Clusterin from BioVendor!
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