Clusterin/apolipoprotein J, its isoforms and Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Milinkeviciute G
PROVIDER: S-EPMC10133478 | biostudies-literature | 2023
REPOSITORIES: biostudies-literature
Publications
Clusterin/apolipoprotein J, its isoforms and Alzheimer's disease.
Milinkeviciute Giedre G Green Kim N KN
Frontiers in aging neuroscience 20230413
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Project description:One of the major challenges in developing effective therapeutic strategies for Alzheimer's disease is understanding how genetic risk factors contribute to neurodegeneration. The apolipoprotein epsilon 4 isoform (APOE4) and variants in the Clusterin (CLU) gene (also known as apolipoprotein J) are associated with increased risk of developing Alzheimer's. Our previous work demonstrated that APOE4 exacerbates synapse degeneration and synaptic accumulation of toxic oligomeric amyloid beta in human Alzheimer's and mouse models of disease. Here, we observe clusterin in synapses in human Alzheimer's disease brain. The percentage of synapses containing clusterin is higher in APOE4 carriers than APOE3 carriers. Furthermore, we observe oligomeric amyloid beta accumulation within synapses containing clusterin which is also higher in APOE4 carriers. These data link two genetic risk factors with synapse degeneration in Alzheimer's and support a potential role for clusterin working with APOE in causing synaptic damage.
| S-EPMC6904249 | biostudies-literature
Project description:Alzheimer's disease (AD) is the most common form of dementia and one of the leading causes of death in the United States. In the past decades, extensive efforts have been devoted to biomarker discovery for early diagnosis and treatment of AD. Herein, this study aims to quantify clusterin (CLU) and apolipoprotein E (APOE) in blood samples from AD patients and evaluate these two proteins as potential biomarkers in AD diagnosis. In-house synthesized 5-plex isotopic N,N-dimethyl leucine (iDiLeu) tags were used to label target peptide standards at different concentrations to construct standard curves. Our study revealed that the levels of CLU and APOE exhibited clear differences in male vs. female AD groups but not in male vs. female non-AD groups. In contrast, the levels of serum CLU and APOE did not show statistically significant differences in the AD groups and non-AD groups. Principal component analysis (PCA) with CLU and APOE showed some separation between the AD and non-AD participants. Significance: Dissecting CLU and APOE heterogeneity in AD pathogenesis may therefore facilitate delineating the pathological relevance for sex-related pathways, leading to personalized medicine in the future. Collectively, this study introduces a cost-effective absolute quantitative proteomics strategy for target protein quantitation and lays the foundation for future investigation of CLU and APOE as potential biomarkers for AD. SIGNIFICANCE STATEMENT: As blood-based biomarkers for AD diagnosis are cost-effective and introduce less invasiveness, discovery and validation of biomarkers in the blood samples of AD patients have become a hot topic in Alzheimer's and dementia research. Thus far, amyloid β (Aβ), total-tau and phosphorylated tau (p-tau) in blood show great accuracy and specificity in diagnosis of AD. However, the underlying mechanism of AD pathology remains to be elusive and complex. Besides these well studied proteins, many other proteins, such as clusterin (CLU) and apolipoprotein E (APOE) have also been found to be related to AD development. It has been implicated that these two proteins are involved in Aβ clearance and deposition. In this study, we measure the absolute concentrations of these two proteins in blood and shed some light on the potential roles of CLU and APOE in AD pathology. Dissecting CLU and APOE heterogeneity in AD pathogenesis may therefore facilitate delineating the pathological relevance for specific pathways between different genders, leading to personalized medicine in the future. Collectively, this study introduces a cost-effective absolute quantitative proteomics strategy for target protein quantitation and lays the foundation for future investigation of CLU and APOE as potential biomarkers for AD.
| S-EPMC8916911 | biostudies-literature
Project description:IntroductionAlzheimer's disease (AD) is the major cause of dementia among the elderly. Finding blood-based biomarkers for disease diagnosis and prognosis is urgently needed.MethodsWe studied protein distributions in brain tissues, cerebrospinal fluid (CSF), and blood of AD patients by using proteomics and a new proteomic method that we call "2D multiplexed Western blot" (2D mxWd). This method allows us to determine in multiple samples the electrophoretic patterns of protein isoforms with different isoelectric points.ResultsApolipoprotein E (ApoE) displays a unique distribution of electrophoretic isoforms in the presence of AD and also a unique pattern specific to the APOE genotype.ConclusionsThe isoelectric distribution of differentially charged ApoE isoforms was used to determine the presence of AD in a small group of samples. Further studies are needed to validate their use as predictors of disease onset and progression, and as biomarkers for determining the efficacy of therapeutic treatments.
| S-EPMC4255367 | biostudies-literature
Project description:Alzheimer’s disease (AD) is the most common form of dementia and one of the leading causes of death in the United States. In past decades, extensive efforts have been devoted to improving our understanding of AD pathogenesis and accelerating biomarker discovery for early diagnosis and clinical treatment of AD. Herein, this study aims to quantify clusterin (CLU) and apolipoprotein E (APOE) in blood samples from AD patients and evaluate these two proteins as potential biomarkers in AD diagnosis. In-house synthesized 5-plex isotopic N,N-dimethyl leucine (iDiLeu) tags were used to label target peptide standards at different concentrations to construct standard curves. Our study reveals that the levels of CLU and APOE exhibit clear disparities in male vs. female AD groups but not in male vs. female non-AD groups, while the levels of serum CLU and APOE do not show statistical differences in the AD groups and non-AD groups. Principal component analysis (PCA) with CLU and APOE showed some separation between the AD and non-AD participants. Significance: Dissecting CLU and APOE heterogeneity in AD pathogenesis may therefore facilitate delineating the pathological relevance for specific pathways between different genders, leading to personalized medicine in the future. Collectively, this study introduces a cost-effective absolute quantitative proteomics strategy for target protein quantitation and lays the foundation for future investigation of CLU and APOE as potential biomarkers for AD.
2022-10-05 | PXD030724 | Pride
Project description: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.
| S-EPMC4106906 | biostudies-literature
Project description:Genetic variation in apolipoprotein E (APOE) influences Alzheimer's disease (AD) risk. APOE ε4 alleles are the strongest genetic risk factor for late onset sporadic AD. The AD risk is dose dependent, as those carrying one APOE ε4 allele have a 2-3-fold increased risk, while those carrying two ε4 alleles have a 10-15-fold increased risk. Individuals carrying APOE ε2 alleles have lower AD risk and those carrying APOE ε3 alleles have neutral risk. APOE is a lipoprotein which functions in lipid transport, metabolism, and inflammatory modulation. Isoform specific effects of APOE within the brain include alterations to Aβ, tau, neuroinflammation, and metabolism. Here we review the association of APOE with AD, the APOE isoform specific effects within brain and periphery, and potential therapeutics.
| S-EPMC8897057 | biostudies-literature
Project description:The minor allele of rs11136000 within CLU is strongly associated with reduced Alzheimer's disease (AD) risk. The mechanism underlying this association is unclear. Here, we report that CLU1 and CLU2 are the two primary CLU isoforms in human brain; CLU1 and CLU2 share exons 2-9 but differ in exon 1 and proximal promoters. The expression of both CLU1 and CLU2 was increased in individuals with significant AD neuropathology. However, only CLU1 was associated with the rs11136000 genotype, with the minor "protective" rs11136000T allele being associated with increased CLU1 expression. Since CLU1 and CLU2 are predicted to encode intracellular and secreted proteins, respectively, we compared their expression; for both CLU1 and CLU2 transfected cells, clusterin is present in the secretory pathway, accumulates in the extracellular media, and is similar in size to clusterin in human brain. Overall, we interpret these results as indicating that the AD-protective minor rs11136000T allele is associated with increased CLU1 expression. Since CLU1 and CLU2 appear to produce similar proteins and are increased in AD, the AD-protection afforded by the rs11136000T allele may reflect increased soluble clusterin throughout life.
| S-EPMC3323613 | biostudies-literature
Project description:Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer's disease (AD). However, the role of CLU on AD pathogenesis is not totally understood. We used cerebrospinal fluid (CSF) and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/amyloid-beta ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p = 3.98 × 10(-7)) and interleukin 6 (IL6, p = 9.94 × 10(-6), in the entire data set and in the APOE ?4- individuals p = 7.40 × 10(-8)). Gene ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration.
| S-EPMC5118651 | biostudies-literature
Project description:While clusterin is reportedly involved in Alzheimer's disease (AD) pathogenesis, how clusterin interacts with amyloid-β (Aß) to cause Aß neurotoxicity remains unclear in vivo. Using 5×FAD transgenic mice, which develop robust AD pathology and memory deficits when very young, we detected interactions between clusterin and Aß in the mouse brains. The two proteins were concurrently upregulated and bound or colocalized with each other in the same complexes or in amyloid plaques. Neuropathology and cognitive performance were assessed in the progeny of clusterin-null mice crossed with 5×FAD mice, yielding clu-/- ;5×FAD and clu+/+ ;5×FAD. We found far less of the various pools of Aß proteins, most strikingly soluble Aß oligomers and amyloid plaques in clu-/- ;5×FAD mice at 5 months of age. At that age, those mice also had higher levels of neuronal and synaptic proteins and better motor coordination, spatial learning and memory than age-matched clu+/+ ;5×FAD mice. However, at 10 months of age, these differences disappeared, with Aß and plaque deposition, neuronal and synaptic proteins and impairment of behavioral and cognitive performance similar in both groups. These findings demonstrate that clusterin is necessarily involved in early stages of AD pathogenesis by enhancing toxic Aß pools to cause Aß-directed neurodegeneration and behavioral and cognitive impairments, but not in late stage.
| S-EPMC8028273 | biostudies-literature
Project description:Clusterin (CLU), or apolipoprotein J (ApoJ), is the third most predominant genetic risk factor associated with late-onset Alzheimer's disease (LOAD). In this study, we use multiple rodent and human brain tissue and neural cell models to demonstrate that CLU is expressed as multiple isoforms that have distinct cellular or subcellular localizations in the brain. Of particular significance, we identify a non-glycosylated 45 kDa CLU isoform (mitoCLU) that is localized to the mitochondrial matrix and expressed in both rodent and human neurons and astrocytes. In addition, we show that rodent mitoCLU is translated from a non-canonical CUG (Leu) start site in Exon 3, a site that coincides with an AUG (Met) in human CLU. Last, we reveal that mitoCLU is present at the gene and protein level in the currently available CLU-/- mouse model. Collectively, these data provide foundational knowledge that is integral in elucidating the relationship between CLU and the development of LOAD.
| S-EPMC6860991 | biostudies-literature