Numerous genetic studies have implicated clusterin, currently No. 3 in AlzGene’s top results, as an Alzheimer’s risk factor, but researchers still know little about how the protein contributes to disease. A brain-imaging study in the December 30 JAMA Neurology online strengthens previous molecular studies that suggest it may mediate Aβ toxicity. Researchers led by Rahul Desikan at the University of California, San Diego, found that a combination of low Aβ42 and high clusterin in the cerebrospinal fluid (CSF) of people without dementia identified those with the earliest signs of brain atrophy as judged by MRI imaging. The association between clusterin and atrophy occurred independently of CSF tau, a marker of neurodegeneration.
The data has sparked interest among other researchers. “This is the first study to relate CSF levels of clusterin to well-established endophenotypes of Alzheimer’s neuropathology,” said Madhav Thambisetty at the National Institute on Aging, Bethesda, Maryland. Simon Lovestone at King’s College London told Alzforum, “This is an important paper. The findings point suggestively to a mechanistic interaction between Aβ and clusterin in the earliest stages of the disease.”
Clusterin, a protein chaperone also known as apolipoprotein J, turns up repeatedly in large genome-wide association studies of Alzheimer’s disease (see Sep 2009 news story; Jun 2010 news story). In addition, previous research has established that clusterin is elevated in brain, blood, and CSF of people with brain amyloid deposits or AD (see Lidström et al., 1998; Nilselid et al., 2006; Jul 2010 news story; and Apr 2011 news story).
Desikan and colleagues wanted to find out how CSF clusterin related to other AD biomarkers. They examined data from 241 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), controlling for variables such as age, sex, ApoE genotype, and severity of cognitive impairment. They did not look at the effect of clusterin risk alleles, but plan to do this in a future study.
At the protein level, the majority of people with high CSF clusterin also had low Aβ. This combination tracked with rapid atrophy of the entorhinal cortex (EC) in 91 participants whose cognition was normal as well as in 150 who were mildly impaired. Many studies suggest the EC is the first brain region affected by Alzheimer’s pathology.
Intriguingly, in the cognitively healthy group, the amount of phosphorylated tau in the CSF showed no correlation with EC atrophy rate. In the MCI cohort, a combination of high CSF p-tau and low Aβ did associate with faster EC atrophy. This result hints that clusterin-associated neurodegeneration precedes tau-associated neurodegeneration, the authors noted. This finding also emphasizes that proteins other than tau affect the way amyloid poisons neurons, Desikan told Alzforum.
Because clusterin correlated with atrophy in the EC but not other brain regions, the protein may play a role in starting neurodegeneration, Desikan speculated. “Clusterin is a lipid-binding protein, and there’s evidence that lipids may be one of the earliest triggers of amyloid-associated neurodegeneration,” he said. Several studies have implicated cholesterol and other lipids in modifying the processing of amyloid precursor protein to jack up production of Aβ (see, e.g., Mar 2008 news story; Feb 2011 news story; Jun 2012 news story). Desikan and colleagues recently found a similar association between fast EC atrophy, low CSF Aβ, and high levels of a different lipid-binding protein, heart fatty acid binding protein (see Desikan et al., 2013). Desikan plans to further investigate the role of this type of protein in early AD by combining CSF and genetic studies. “We hope this work will spur initiatives to look at other proteins that affect early Aβ-associated neurotoxicity. If we can get a better handle on the biology, we may get a window into a modifiable target,” he suggested.
How might clusterin influence neurodegeneration? While the CSF study cannot answer this question, animal work suggests that the protein renders Aβ toxic by promoting oligomerization (see Jul 2002 news story; Dec 2011 news story). Alternatively, Lovestone and colleagues reported that clusterin mediates Aβ toxicity and cell death through a Wnt signaling pathway (see Dec 2012 news story). In addition, Lovestone found that adding Aβ pumps up intracellular clusterin levels in cultured neurons, suggesting a feedback loop. The new CSF study dovetails with these cell-based studies, Lovestone noted. “It adds weight to the hypothesis that elevation of clusterin is both an early effect, and an early mediator, of Aβ-induced disease,” he told Alzforum.
Clusterin affects many cellular processes, including inflammation, so it may influence AD through multiple means, Thambisetty pointed out. In the December 30 Journal of Biological Chemistry, researchers led by Johannes Nimpf at the Medical University of Vienna add yet another possible mechanism. They report that extracellular clusterin triggers proliferation of neuronal precursors in the brain, suggesting that the protein serves to maintain neurogenesis.
With an apparent role in early AD, does clusterin show promise as a biomarker or therapeutic target? If the current findings replicate in a larger cohort, researchers should test whether combining CSF clusterin with Aβ42 helps identify those people most likely to progress to AD, Thambisetty suggested. However, Lovestone noted that the effect size of clusterin in the current study appears quite modest, implying that it might add little to current biomarkers. With regard to therapy, commentators agreed that its many roles would make clusterin itself difficult to target. Instead, the pathway induced by clusterin might offer better potential, Lovestone suggested.—Madolyn Bowman Rogers
- Paper Alert: GWAS Hits Clusterin, CR1, PICALM Formally Published
- Repeat Offenders—CLU, CR1, PICALM Hold Up in Association Studies
- Research Brief: Clusterin Grabs Spotlight Among Elite Few LOAD Genes
- Research Brief: Link Tightens Between Plasma Clusterin and AD
- Research Brief: Flotillin, Cholesterol Aid APP Endocytosis, Processing
- A Surfeit of Sphingolipids Sours Aβ Digestion
- Cholesterol Binds APP Fragment, May Direct It to Lipid Rafts
- Stockholm: Clusterin (or Beware the Evil Chaperone!)
- Keeping It Under Wraps: Clusterin Encases Aβ Oligomers In Vitro
- Getting a CLU—Does Genetic Risk Factor Mediate Aβ Toxicity?
- Lidström AM, Bogdanovic N, Hesse C, Volkman I, Davidsson P, Blennow K. Clusterin (apolipoprotein J) protein levels are increased in hippocampus and in frontal cortex in Alzheimer's disease. Exp Neurol. 1998 Dec;154(2):511-21. PubMed.
- Nilselid AM, Davidsson P, Nägga K, Andreasen N, Fredman P, Blennow K. Clusterin in cerebrospinal fluid: analysis of carbohydrates and quantification of native and glycosylated forms. Neurochem Int. 2006 Jun;48(8):718-28. PubMed.
- Desikan RS, Thompson WK, Holland D, Hess CP, Brewer JB, Zetterberg H, Blennow K, Andreassen OA, McEvoy LK, Hyman BT, Dale AM, . Heart fatty acid binding protein and Abeta-associated Alzheimer's neurodegeneration. Mol Neurodegener. 2013;8(1):39. PubMed.
- Desikan RS, Thompson WK, Holland D, Hess CP, Brewer JB, Zetterberg H, Blennow K, Andreassen OA, McEvoy LK, Hyman BT, Dale AM, Alzheimer’s Disease Neuroimaging Initiative Group. The role of clusterin in amyloid-β-associated neurodegeneration. JAMA Neurol. 2014 Feb;71(2):180-7. PubMed.
- Leeb C, Eresheim C, Nimpf J. Clusterin is a ligand for apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR) and signals via the Reelin-signaling pathway. J Biol Chem. 2014 Feb 14;289(7):4161-72. Epub 2013 Dec 31 PubMed.