Clusterin: A forgotten player in Alzheimer's disease

Abstract

Clusterin, also known as apolipoprotein J, is a versatile chaperone molecule which contains several amphipathic and coiled-coil alpha-helices, typical characteristics of small heat shock proteins. In addition, clusterin has three large intrinsic disordered regions, so-called molten globule domains, which can stabilize stressed protein structures. Twenty years ago, it was demonstrated that the expression of clusterin was clearly increased in Alzheimer's disease (AD). Later it was observed that clusterin can bind amyloid-beta peptides and prevent their fibrillization. Clusterin is also involved in the clearance of amyloid-beta peptides and fibrils by binding to megalin receptors and enhancing their endocytosis within glial cells. Clusterin is a complement inhibitor and can suppress complement activation observed in AD. Clusterin is also present in lipoprotein particles and regulates cholesterol and lipid metabolism of brain which is disturbed in AD. Clusterin is a stress-induced chaperone which is normally secreted but in conditions of cellular stress, it can be transported to cytoplasm where it can bind to Bax protein and inhibit neuronal apoptosis. Clusterin can also bind to Smad2/3 proteins and potentiate the neuroprotective TGFbeta signaling. An alternative splicing can produce a variant isoform of clusterin which can be translocated to nuclei where it induces apoptosis. The role of nuclear clusterin in AD needs to be elucidated. We will review here the extensive literature…