title: Intracellular clusterin interacts with brain isoforms of the bridging integrator 1 and with the microtubule-associated protein Tau in Alzheimer's disease.
abstract: Sporadic or late-onset Alzheimer's disease (AD) is expected to affect 50% of individuals reaching 85 years of age. The most significant genetic risk factor for late-onset AD is the e4 allele of APOE gene encoding apolipoprotein E, a lipid carrier shown to modulate brain amyloid burden. Recent genome-wide association studies have uncovered additional single nucleotide polymorphisms (SNPs) linked to AD susceptibility, including those in the CLU and BIN1 genes encoding for clusterin (CLU) and the bridging integrator 1 (BIN1) proteins, respectively. Because CLU has been implicated in brain amyloid-β (Aβ) clearance in mouse models of amyloid deposition, we sought to investigate whether an AD-linked SNP in the CLU gene altered Aβ42 biomarker levels in the cerebrospinal fluid (CSF). Instead, we found that the CLU rs11136000 SNP modified CSF levels of the microtubule-associated protein Tau in AD patients. We also found that an intracellular form of CLU (iCLU) was upregulated in the brain of Tau overexpressing Tg4510 mice, but not in Tg2576 amyloid mouse model. By overexpressing iCLU and Tau in cell culture systems we discovered that iCLU was a Tau-interacting protein and that iCLU associated with brain-specific isoforms of BIN1, also recently identified as a Tau-binding protein. Through expression analysis of CLU and BIN1 variants, we found that CLU and BIN1 interacted via their coiled-coil motifs. In co-immunoprecipitation studies using human brain tissue, we showed that iCLU and the major BIN1 isoform expressed in neurons were associated with modified Tau species found in AD. Finally, we showed that expression of certain coding CLU variants linked to AD risk led to increased levels of iCLU. Together, our findings suggest that iCLU and BIN1 interaction might impact Tau function in neurons and uncover potential new mechanisms underlying the etiology of Tau pathology in AD.
authors: Department of Neuroscience, Early Development and Discovery Sciences, Merck Research Laboratories, Merck Sharp & Dohme Corp., West Point, Pennsylvania, United States of America.
authors: Yuan
authors: Y
authors: Zhou
authors: Department of Neuroscience, Early Development and Discovery Sciences, Merck Research Laboratories, Merck Sharp & Dohme Corp., West Point, Pennsylvania, United States of America.
authors: Ikuo
authors: I
authors: Hayashi
authors: Department of Neuroscience, Early Development and Discovery Sciences, Merck Research Laboratories, Merck Sharp & Dohme Corp., West Point, Pennsylvania, United States of America.
authors: Jacky
authors: J
authors: Wong
authors: Department of Neuroscience, Early Development and Discovery Sciences, Merck Research Laboratories, Merck Sharp & Dohme Corp., West Point, Pennsylvania, United States of America.
authors: Katherine
authors: K
authors: Tugusheva
authors: Department of Neuroscience, Early Development and Discovery Sciences, Merck Research Laboratories, Merck Sharp & Dohme Corp., West Point, Pennsylvania, United States of America.
authors: John J
authors: JJ
authors: Renger
authors: Department of Neuroscience, Early Development and Discovery Sciences, Merck Research Laboratories, Merck Sharp & Dohme Corp., West Point, Pennsylvania, United States of America.
authors: Celina
authors: C
authors: Zerbinatti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D051152:Clusterin / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D060066:Protein Interaction Maps; D020033:Protein Isoforms / Q000032:analysis / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D016875:tau Proteins / Q000032:analysis / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C101410:BIN1 protein, human; D051152:Clusterin; D009687:Nuclear Proteins; D020033:Protein Isoforms; D025521:Tumor Suppressor Proteins; D016875:tau Proteins