Clusterin in Alzheimer’s Disease: Mechanisms, Genetics, and Lessons From Other Pathologies

Abstract

Clusterin (CLU) or APOJ is a multifunctional glycoprotein that has been implicated in several physiological and pathological states, including Alzheimer’s disease (AD). With a prominent extracellular chaperone function, additional roles have been discussed for clusterin, including lipid transport and immune modulation, and it is involved in pathways common to several diseases such as cell death and survival, oxidative stress, and proteotoxic stress. Although clusterin is normally a secreted protein, it has also been found intracellularly under certain stress conditions. Multiple hypotheses have been proposed regarding the origin of intracellular clusterin, including specific biogenic processes leading to alternative transcripts and protein isoforms, but these lines of research are incomplete and contradictory. Current consensus is that intracellular clusterin is most likely to have exited the secretory pathway at some point or to have re-entered the cell after secretion. Clusterin’s relationship with amyloid beta (Aβ) has been of great interest to the AD field, including clusterin’s apparent role in altering Aβ aggregation and/or clearance. Additionally, clusterin has been more recently identified as a mediator of Aβ toxicity, as evidenced by the neuroprotective effect of CLU knockdown and knockout in rodent and human iPSC-derived neurons. CLU is also the third most significant genetic risk factor for late onset AD and several variants have been identified in CLU . Although the exact contribution of these variants to altered AD risk is unclear, some have been linked to altered CLU expression at both mRNA and protein levels, altered cognitive and memory function, and altered brain structure. The apparent complexity of clusterin’s biogenesis, the lack of clarity over the origin of the intracellular clusterin species, and the number of pathophysiological functions attributed to clusterin have all contributed to the challenge of understanding the role of clusterin in AD pathophysiology. Here, we highlight clusterin’s relevance to AD by discussing the evidence linking clusterin to AD, as well as drawing parallels on how the role of clusterin in other diseases and pathways may help us understand its biological function(s) in association with AD.

Apolipoprotein J is a hepatokine regulating muscle glucose metabolism and insulin sensitivity

“…Apolipoprotein J (ApoJ, also called clusterin) was first described as a secreted sulfated glycoprotein that is ubiquitously found in metabolic tissues and body fluids 14 . ApoJ exists as multiple protein isoforms including the 75-80 kDa highly glycosylated secreted form, and the smaller intracellular forms that are not well characterized 15,16 . The secretory isoform of ApoJ is thought to have molecular chaperone activity depending on the degree of glycosylation 17,18 and binds to specific cell surface receptors in mediating its biological effects, such as endocytosis 19,20 .…”

“…The secretory isoform of ApoJ is thought to have molecular chaperone activity depending on the degree of glycosylation 17,18 and binds to specific cell surface receptors in mediating its biological effects, such as endocytosis 19,20 . Although the exact role of ApoJ in many conditions remains unclear 15 , ApoJ has been implicated in altered pathophysiologic disorders, including atherosclerosis 21 , obesity 22 , diabetes 23 , and Alzheimer's disease 24 .…”

scGRNom: a computational pipeline of integrative multi-omics analyses for predicting cell-type disease genes and regulatory networks

“…Like BIN1, it is a key marker gene as well, and it is screened for AD patients to determine the progression of the disease clinically [88]. Mechanistically, the function of CLU remains unclear and conflicting prevailing theories as to the exact method of progression remain unanswered [91]; at a broader level, however, the interaction between APOE and CLU is certain. Instances of functionally conserved genes were documented as well.…”

Upcoming diagnostic biomarkers with promising prospects in neurological disorders

“…An ubiquitously and constitutively expressed protein present in bodily fluids and a varied range of tissues is clusterin. Its extensive expression is joined by numerous ascribed functions which include inhibition of the chaperone function, lipid transport, complement system and regulation of cell survival and cell death pathways . Advanced research established that clusterin might amalgamate with amyloid‐β (Aβ) peptides and avert fibril formation.…”