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.
Highlights
Multiple genome-wide association studies (GWAS) have replicated a link between common single nucleotide polymorphisms in the CLU gene and increased susceptibility for late-onset Alzheimer’s disease (AD) [1,2,3,4,5,6,7]
When stratified by rs11136000 and APOE genotypes, we found a significant effect of the risk allele C on cerebrospinal fluid (CSF) Tau levels in AD patients carrying apoE4, with homozygous CC individuals showing significantly higher CSF Tau than heterozygous CT carriers (Fig. 1c)
It has been recently reported that elevated CSF clusterin contributes to entorhinal atrophy in patients with mild cognitive impairment and increased Ab42 deposition [52], suggesting that clusterin might be involved in AD pathogenesis
Summary
Multiple genome-wide association studies (GWAS) have replicated a link between common single nucleotide polymorphisms in the CLU gene (rs11136000 and rs1532278) and increased susceptibility for late-onset Alzheimer’s disease (AD) [1,2,3,4,5,6,7]. Clusterin (CLU) is synthesized as a 60–80 kD precursor protein that undergoes internal cleavage generating a- and b-chains joined by disulfide bonds [10]. This glycosylated heterodimeric CLU is constitutively secreted and referred to as soluble clusterin (sCLU), or as apolipoprotein J (apoJ), when found in association with lipoproteins [11]. Of relevance to AD, it has been recently shown that iCLU levels increase quickly in cultured primary neurons exposed to amyloid-b peptides (Ab), and that this iCLU elevation is required for the neurotoxic downstream signaling effects of Ab [17]
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