Clusterin: a multifaceted protein in the brain

Late-onset Alzheimer’s disease (LOAD), the most common cause of dementia, currently affects 5.6 million Americans ages 65 and older. LOAD is a neurodegenerative disorder characterized by progressive loss in synaptic function, notable bioenergetic decl ine, increased neuronal death and brain atrophy, and significant cognitive impairment. Because the etiology of LOAD remains unknown, a treatment for LOAD has not yet been formulated, a fact that is clearly demonstrated by the more than 200 failed clinical trials. These failures underscore the significance of identifying the LOAD risk mechanisms that would allow early intervention in the preclinical stage of LOAD. Genome-wide association studies have identified more than a dozen genetic risk variants that are associated with the development of LOAD. Clusterin (CLU), also known as apolipoprotein J (APOJ), has been established as the third most prominent genetic risk factor for LOAD after apolipoprotein E (APOE) and bridging integrator 1 (BIN1) (Harold et al., 2009; Lambert et al., 2009). A number of single nucleotide polymorphisms (SNPs) within the CLU locus, with the majority being intronic, have been linked to significantly altered LOAD risk, independent of APOE status (Figure 1A; (Medical Genetics and Human Variation, 2019)); however, it is unclear how these SNPs affect CLU mRNA, protein isoform expression and function.