Редактирование: CLU

Clusterin precursor (Aging-associated gene 4 protein) (Apolipoprotein J) (Apo-J) (Complement cytolysis inhibitor) (CLI) (Complement-associated protein SP-40,40) (Ku70-binding protein 1) (NA1/NA2) (Sulfated glycoprotein 2) (SGP-2) (Testosterone-repressed prostate message 2) (TRPM-2) [Contains: Clusterin beta chain (ApoJalpha) (Complement cytolysis inhibitor a chain); Clusterin alpha chain (ApoJbeta) (Complement cytolysis inhibitor b chain)] [APOJ] [CLI] [KUB1] [AAG4]

==Publications==

{{medline-entry
|title=Single Nucleotide Polymorphisms in Alzheimer's Disease Risk Genes Are Associated with Intrinsic Connectivity in Middle Age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32986668
|abstract=It is critical to identify individuals at risk for Alzheimer's disease (AD) earlier in the disease time course, such as middle age and preferably well prior to the onset of clinical symptoms, when intervention efforts may be more successful. Genome-wide association and candidate gene studies have identified single nucleotide polymorphisms (SNPs) in [[APOE]], [[CLU]], [[CR1]], [[PICALM]], and [[SORL1]] that confer increased risk of AD. In the current study, we investigated the associations between SNPs in these genes and resting-state functional connectivity within the default mode network (DMN), frontoparietal network (FPN), and executive control network (ECN) in healthy, non-demented middle-aged adults (age 40 -60; N = 123; 74 females). Resting state networks of interest were identified through independent components analysis using a template-matching procedure and individual spatial maps and time courses were extracted using dual regression. Within the posterior DMN, functional connectivity was associated with [[CR1]] rs1408077 and [[CLU]] rs9331888 polymorphisms (p's < 0.05). FPN connectivity was associated with [[CR1]] rs1408077, [[CLU]] rs1136000, [[SORL1]] rs641120, and [[SORL1]] rs689021 (p's < 0.05). Functional connectivity within the ECN was associated with the [[CLU]] rs11136000 (p < 0.05). There were no [[APOE]]- or [[PICALM]]-related differences in any of the networks investigated (p's > 0.05). This is the first demonstration of the relationship between intrinsic network connectivity and AD risk alleles in [[CLU]], [[CR1]], and [[SORL1]] in healthy, middle-aged adults. These SNPs should be considered in future investigations aimed at identifying potential preclinical biomarkers for AD.

|keywords=* Aging
* Alzheimer’s disease
* middle aged
* neuroimaging
* single nucleotide 
polymorphism
|full-text-url=https://sci-hub.do/10.3233/JAD-200444
}}
{{medline-entry
|title=Expression of Clusterin suppresses Cr(VI)-induced premature senescence through activation of PI3K/AKT pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31376806
|abstract=Our group found that long-term low-dose exposure to hexavalent chromium [Cr(VI)] in L-02 hepatocytes resulted in premature senescence, which accompanied by the increased expression of Clusterin ([[CLU]]), but the functional role of [[CLU]] in premature senescence has never been explored. In the present study, the [[CLU]] overexpressed or silenced L-02 hepatocytes were established by lentiviral vector transfection. Cell viability assay, cell cycle analysis, western blotting, plate clone formation assay, and confocal microcopy were performed. The results indicated that Cr(VI)-induced premature senescence was associated with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway inhibition, and high expression of [[CLU]] in the senescent cells exerted its functional role of promoting cell proliferation. [[CLU]] could complex with eukaryotic translation initiation factor 3 subunit I (EIF3I) and prevent its degradation, leading to the increase of AKT activity in Cr(VI)-exposed senescent hepatocytes. Blockage of the PI3K/AKT pathway with its inhibitor LY294002 eliminated the inhibitory effect of [[CLU]] on Cr(VI)-induced premature senescence. We concluded that high expression of [[CLU]] suppressed Cr(VI)-induced premature senescence through activation of PI3K/AKT pathway, which will provide the experimental basis for the study of Cr(VI)-induced liver cancer, especially for the elucidation of the mechanism of liver cancer cells escaping from senescence.
|mesh-terms=* Cell Line
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Chromium
* Clusterin
* Hepatocytes
* Humans
* Phosphatidylinositol 3-Kinase
* Proto-Oncogene Proteins c-akt
* Signal Transduction
|keywords=* Clusterin (CLU)
* Hexavalent chromium [Cr(VI)]
* L-02 hepatocytes
* Phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (AKT)
* Premature senescence
|full-text-url=https://sci-hub.do/10.1016/j.ecoenv.2019.109465
}}
{{medline-entry
|title=Informative combination of [[CLU]] rs11136000, serum HDL levels, diabetes, and age as a new piece of puzzle-picture of predictive medicine for cognitive disorders.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30560405
|abstract=Clusterin ([[CLU]]) is the third most important associated risk gene in cognitive disorders. Regarding the controversy about the association of [[CLU]] rs11136000 with mild cognitive impairment (MCI), the aim of this study was to investigate a putative association of [[CLU]] rs11136000 with MCI as well as the serum biological factors with a special attention to the age as a main dimension of a multifactorial elderly disease in an Iranian elderly cohort in which the mentioned association was not previously investigated. The study also checked the association between diabetes and MCI in this population. A population of 418 individuals containing 236 MCI and 192 control subjects was recruited from the Amirkola health and aging population cohort. Serum biological indexes were assessed by biochemical and enzyme-linked immunosorbent assay, and rs11136000 genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. Bioinformatics analyses were used to identify the putative effect of rs11136000 on the secondary structure of RNA and chromatin location in different cell lines and tissues. Type 2 diabetes was present with a higher proportion in the MCI group in comparison with the control group (P = 0.041). The frequency of the C allele of [[CLU]] rs11136000 was significantly different between cases and controls and was associated with MCI risk (OR 1.79, P = 0.019). Under a dominant genetic model, the CC genotype showed a predisposing effect in individuals aged ≥ 75 years (OR 3.33, P = 0.0004). Interestingly, under an over-dominant model, the CT genotype had a protective effect in this population (OR 4.52, P = < 0.0001). We also found a significant association between the genotypes and high-density lipoprotein (HDL) levels in MCI patients (P = 0.0004). Bioinformatics analysis showed that rs11136000 is located in the transcribed region without any regulatory features such as being enhancer or insulator. Also, the T>C transition of [[CLU]] rs11136000 could not cause significant mRNA folding (P = 0.950). Contrary to other studies on Asian populations, this study demonstrated an association between rs11136000 and MCI in an elderly Iranian population. This study also suggests that an age-dependent approach to the previous studies may be performed in order to revise the previous belief in this geographical area. The rs11136000 genotypes in combination with HDL levels and knowledge about diabetes background may be used as a predictive medicine tool for cognitive disorders.
|mesh-terms=* Age Factors
* Aged
* Aging
* Blood Glucose
* Case-Control Studies
* Cell Line
* Clusterin
* Cognition Disorders
* Diabetes Mellitus
* Female
* Gene Frequency
* Genetic Loci
* Genetic Predisposition to Disease
* Genome-Wide Association Study
* Humans
* Lipoproteins, HDL
* Male
* Polymorphism, Single Nucleotide
|keywords=* Age
* Clusterin
* HDL
* Mild cognitive impairment
* Predictive medicine
* Rs11136000
|full-text-url=https://sci-hub.do/10.1007/s11033-018-4561-5
}}
{{medline-entry
|title=Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer's disease susceptibility.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30297968
|abstract=Here we use deep sequencing to identify sources of variation in mRNA splicing in the dorsolateral prefrontal cortex (DLPFC) of 450 subjects from two aging cohorts. Hundreds of aberrant pre-mRNA splicing events are reproducibly associated with Alzheimer's disease. We also generate a catalog of splicing quantitative trait loci (sQTL) effects: splicing of 3,006 genes is influenced by genetic variation. We report that altered splicing is the mechanism for the effects of the [[PICALM]], [[CLU]] and [[PTK2B]] susceptibility alleles. Furthermore, we performed a transcriptome-wide association study and identified 21 genes with significant associations with Alzheimer's disease, many of which are found in known loci, whereas 8 are in novel loci. These results highlight the convergence of old and new genes associated with Alzheimer's disease in autophagy-lysosomal-related pathways. Overall, this study of the transcriptome of the aging brain provides evidence that dysregulation of mRNA splicing is a feature of Alzheimer's disease and is, in some cases, genetically driven.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alternative Splicing
* Alzheimer Disease
* Brain
* Chromosome Mapping
* Cohort Studies
* Female
* Gene Expression Profiling
* Genetic Predisposition to Disease
* Genome-Wide Association Study
* Humans
* Male
* Quantitative Trait Loci
* RNA Splicing
* Systems Biology
* Systems Integration
* Transcriptome

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354244
}}
{{medline-entry
|title=DNA methylation analysis on purified neurons and glia dissects age and Alzheimer's disease-specific changes in the human cortex.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30045751
|abstract=Epigenome-wide association studies (EWAS) based on human brain samples allow a deep and direct understanding of epigenetic dysregulation in Alzheimer's disease (AD). However, strong variation of cell-type proportions across brain tissue samples represents a significant source of data noise. Here, we report the first EWAS based on sorted neuronal and non-neuronal (mostly glia) nuclei from postmortem human brain tissues. We show that cell sorting strongly enhances the robust detection of disease-related DNA methylation changes even in a relatively small cohort. We identify numerous genes with cell-type-specific methylation signatures and document differential methylation dynamics associated with aging specifically in neurons such as [[CLU]], [[SYNJ2]] and [[NCOR2]] or in glia [[RAI1]],CXXC5 and [[INPP5A]]. Further, we found neuron or glia-specific associations with AD Braak stage progression at genes such as [[MCF2L]], [[ANK1]], [[MAP2]], [[LRRC8B]], [[STK32C]] and [[S100B]]. A comparison of our study with previous tissue-based EWAS validates multiple AD-associated DNA methylation signals and additionally specifies their origin to neuron, e.g., [[HOXA3]] or glia ([[ANK1]]). In a meta-analysis, we reveal two novel previously unrecognized methylation changes at the key AD risk genes [[APP]] and [[ADAM17]]. Our data highlight the complex interplay between disease, age and cell-type-specific methylation changes in AD risk genes thus offering new perspectives for the validation and interpretation of large EWAS results.
|mesh-terms=* ADAM17 Protein
* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Autopsy
* Cell Separation
* DNA Methylation
* Epigenesis, Genetic
* Epigenomics
* Genetic Predisposition to Disease
* Genome-Wide Association Study
* Humans
* Neuroglia
* Neurons
* Organ Specificity
* Transcriptome
|keywords=* Aging
* Alzheimer’s disease
* Brain
* Cell sorting
* DNA methylation
* EWAS
* Epigenetics
* Glia
* Neurodegeneration
* Neuron
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058387
}}
{{medline-entry
|title=Recent studies on cellular and molecular mechanisms in Alzheimer's disease: focus on epigenetic factors and histone deacetylase.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/29397389
|abstract=Alzheimer's disease (AD) is one of the most common neurodegenerative disorders mainly affecting elderly people. It is characterized by progressive loss of memory and cognitive function. More than 95% of AD cases are related to sporadic or late-onset AD (LOAD). The etiology of LOAD is still unclear. It has been reported that environmental factors and epigenetic alterations play a significant role in AD pathogenesis. Furthermore, recently, genome-wide association studies (GWAS) identified 10 novel risk genes: [[ABCA7]], [[APOE]], [[BIN1]], [[CD2AP]], [[CD33]], [[CLU]], [[CR1]], [[MS4A6A]], [[MS4A4E]], and [[PICALM]], which play an important role for LOAD. In this review, the therapeutic approaches of AD by epigenetic modifications have been discussed. Nowadays, HDAC inhibitors have clinically proven its activity for epigenetic modifications. Furthermore, we try to establish the relationship between HDAC inhibitors and above mentioned LOAD risk genes. Finally, we are hoping that this review may open new area of research for AD treatment.
|mesh-terms=* Aging
* Alzheimer Disease
* Animals
* Cognition Disorders
* Epigenesis, Genetic
* Genetic Predisposition to Disease
* Genome-Wide Association Study
* Histone Deacetylase Inhibitors
* Histone Deacetylases
* Humans
|keywords=* Alzheimer’s disease
* GWAS
* HDAC inhibitors
* LOAD
* epigenetic modification
|full-text-url=https://sci-hub.do/10.1515/revneuro-2017-0049
}}
{{medline-entry
|title=Role of [[CLU]], [[PICALM]], and [[TNK1]] Genotypes in Aging With and Without Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28631188
|abstract=Healthy and impaired cognitive aging may be associated to different prevalences of single-nucleotide polymorphisms (SNPs). In a multicenter case-control association study, we studied the SNPs rs11136000 (clusterin, [[CLU]]), rs541458 (phosphatidylinositol binding clatrin assembly protein, [[PICALM]]), and rs1554948 (transcription factor A, and tyrosine kinase, non-receptor, 1, [[TNK1]]) according to the three age groups 50-65 years (group 1), 66-80 years (group 2), and 80  years (group 3) in 569 older subjects without cognitive impairment (NoCI) and 520 Alzheimer's disease (AD) patients. In NoCI subjects, a regression analysis suggested a relationship between age and [[TNK1]] genotypes, with the [[TNK1]]-A/A genotype frequency that increased with higher age, and resulting in a different distribution of the [[TNK1]]-A allele. In AD patients, a regression analysis suggested a relationship between age and [[PICALM]] genotypes and [[TNK1]] genotypes, with the [[PICALM]]-T/C and [[TNK1]]-A/A genotype frequencies that decreased with increasing age. A resulting difference in the distribution of [[PICALM]]-C allele and [[TNK1]]-A allele was also observed. The [[TNK1]]-A allele was overrepresented in NoCI subjects than in AD patients in age groups 2 and 3. These results confirmed after adjustment for apolipoprotein E polymorphism, which suggested a different role of [[PICALM]] and [[TNK1]] in healthy and impaired cognitive aging. More studies, however, are needed to confirm the observed associations.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alleles
* Alzheimer Disease
* Clusterin
* Cohort Studies
* Female
* Fetal Proteins
* Gene Frequency
* Genetic Predisposition to Disease
* Humans
* Male
* Middle Aged
* Monomeric Clathrin Assembly Proteins
* Polymorphism, Single Nucleotide
* Protein-Tyrosine Kinases
|keywords=* Alzheimer’s disease
* Biogerontology
* Brain aging
* Cognition
* Dementia
* Genetics
|full-text-url=https://sci-hub.do/10.1007/s12035-017-0547-x
}}
{{medline-entry
|title=Late Onset Alzheimer's Disease Risk Variants in Cognitive Decline: The PATH Through Life Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28269768
|abstract=Recent genome wide association studies have identified a number of single nucleotide polymorphisms associated with late onset Alzheimer's disease (LOAD). We examined the associations of 24 LOAD risk loci, individually and collectively as a genetic risk score, with cognitive function. We used data from 1,626 non-demented older Australians of European ancestry who were examined up to four times over 12 years on tests assessing episodic memory, working memory, vocabulary, and information processing speed. Linear mixed models were generated to examine associations between genetic factors and cognitive performance. Twelve SNPs were significantly associated with baseline cognitive performance ([[ABCA7]], [[MS4A4E]], SORL1), linear rate of change (APOE, [[ABCA7]], [[INPP5D]], [[ZCWPW1]], CELF1), or quadratic rate of change (APOE, [[CLU]], [[EPHA1]], [[HLA-DRB5]], [[INPP5D]], FERMT2). In addition, a weighted genetic risk score was associated with linear rate of change in episodic memory and information processing speed. Our results suggest that a minority of AD related SNPs may be associated with non-clinical cognitive decline. Further research is required to verify these results and to examine the effect of preclinical AD in genetic association studies of cognitive decline. The identification of LOAD risk loci associated with non-clinical cognitive performance may help in screening for individuals at greater risk of cognitive decline.
|mesh-terms=* Age of Onset
* Alzheimer Disease
* Australia
* Cognitive Dysfunction
* European Continental Ancestry Group
* Female
* Genetic Association Studies
* Genetic Loci
* Genetic Predisposition to Disease
* Humans
* Linear Models
* Longitudinal Studies
* Male
* Middle Aged
* Neuropsychological Tests
* Polymorphism, Single Nucleotide
|keywords=* Alzheimer’s disease
* cognitive aging
* genetic epidemiology
* genetic risk scores
* longitudinal studies
* single nucleotide polymorphisms
|full-text-url=https://sci-hub.do/10.3233/JAD-160774
}}
{{medline-entry
|title=Association and interaction effects of Alzheimer's disease-associated genes and lifestyle on cognitive aging in older adults in a Taiwanese population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28199971
|abstract=Genome-wide association studies and meta-analyses implicated that increased risk of developing Alzheimer's diseases (AD) has been associated with the [[ABCA7]], [[APOE]], [[BIN1]], [[CASS4]], [[CD2AP]], [[CD33]], [[CELF1]], [[CLU]], [[CR1]], [[DSG2]], [[EPHA1]], [[FERMT2]], [[HLA-DRB1]], [[HLA-DRB4]], [[INPP5D]], [[MEF2C]], [[MS4A4A]], [[MS4A4E]], [[MS4A6E]], [[NME8]], [[PICALM]], [[PLD3]], [[PTK2B]], [[RIN3]], [[SLC24A4]], [[SORL1]], and [[ZCWPW1]] genes. In this study, we assessed whether single nucleotide polymorphisms (SNPs) within these 27 AD-associatedgenes are linked with cognitive aging independently and/or through complex interactions in an older Taiwanese population. We also analyzed the interactions between lifestyle and these genes in influencing cognitive aging. A total of 634 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examination (MMSE) scores were performed for all subjects to evaluate cognitive functions. Out of the 588 SNPs tested in this study, only the association between [[CASS4]]-rs911159 and cognitive aging persisted significantly (P = 2.2 x 10-5) after Bonferroni correction. Our data also showed a nominal association of cognitive aging with the SNPs in six more key AD-associated genes, including [[EPHA1]]-rs10952552, [[FERMT2]]-rs4901317, [[MEF2C]]-rs9293506, [[PLD3]]-rs11672825, [[RIN3]]-rs1885747, and [[SLC24A4]]-rs67063100 (P = 0.0018~0.0097). Additionally, we found the interactions among [[CASS4]]-rs911159, EPHA-rs10952552, [[FERMT2]]-rs4901317, [[MEF2C]]-rs9293506, or [[SLC24A4]]-rs67063100 on cognitive aging (P = 0.004~0.035). Moreover, our analysis suggested the interactions of [[SLC24A4]]-rs67063100 or [[MEF2C]]-rs9293506 with lifestyle such as alcohol consumption, smoking status, physical activity, or social support on cognitive aging (P = 0.008~0.041). Our study indicates that the AD-associated genes may contribute to the risk of cognitive aging independently as well as through gene-gene and gene-lifestyle interactions.
|mesh-terms=* Age Factors
* Aged
* Alleles
* Alzheimer Disease
* Cognitive Aging
* Epistasis, Genetic
* Female
* Gene-Environment Interaction
* Genetic Association Studies
* Genetic Predisposition to Disease
* Humans
* Life Style
* Male
* Middle Aged
* Polymorphism, Single Nucleotide
* Risk Factors
* Taiwan
|keywords=* Alzheimer’s diseases
* Gerotarget
* Mini-Mental State Examination
* cognitive aging
* gene-gene and gene-lifestyle interactions
* single nucleotide polymorphisms
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421828
}}
{{medline-entry
|title=An Alzheimer's Disease Genetic Risk Score Predicts Longitudinal Thinning of Hippocampal Complex Subregions in Healthy Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27482534
|abstract=Variants at 21 genetic loci have been associated with an increased risk for Alzheimer's disease (AD). An important unresolved question is whether multiple genetic risk factors can be combined to increase the power to detect changes in neuroimaging biomarkers for AD. We acquired high-resolution structural images of the hippocampus in 66 healthy, older human subjects. For 45 of these subjects, longitudinal 2-year follow-up data were also available. We calculated an additive AD genetic risk score for each participant and contrasted this with a weighted risk score (WRS) approach. Each score included [[APOE]] (apolipoprotein E), [[CLU]] (clusterin), [[PICALM]] (phosphatidylinositol binding clathrin assembly protein), and family history of AD. Both unweighted risk score (URS) and WRS correlated strongly with the percentage change in thickness across the whole hippocampal complex (URS: r = -0.40; p = 0.003; WRS: r = -0.25, p = 0.048), driven by a strong relationship to entorhinal cortex thinning (URS: r = -0.35; p = 0.009; WRS: r = -0.35, p = 0.009). By contrast, at baseline the risk scores showed no relationship to thickness in any hippocampal complex subregion. These results provide compelling evidence that polygenic AD risk scores may be especially sensitive to structural change over time in regions affected early in AD, like the hippocampus and adjacent entorhinal cortex. This work also supports the paradigm of studying genetic risk for disease in healthy volunteers. Together, these findings will inform clinical trial design by supporting the idea that genetic prescreening in healthy control subjects can be useful to maximize the ability to detect an effect on a longitudinal neuroimaging endpoint, like hippocampal complex cortical thickness.
|mesh-terms=* Aging
* Alzheimer Disease
* Apolipoproteins E
* Clinical Trials as Topic
* Clusterin
* European Continental Ancestry Group
* Female
* Follow-Up Studies
* Genetic Predisposition to Disease
* Hippocampus
* Humans
* Longitudinal Studies
* Magnetic Resonance Imaging
* Male
* Mental Status Schedule
* Middle Aged
* Monomeric Clathrin Assembly Proteins
* Multifactorial Inheritance
* Multivariate Analysis
* Neuropsychological Tests
* Organ Size
* Prodromal Symptoms
|keywords=* clinical trials
* normal aging
* polygenic risk score
* preclinical Alzheimer's disease
* structural MRI
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945997
}}
{{medline-entry
|title=Genetically-mediated Grey and White Matter Alteration in Normal Elderly Individuals with the [[CLU]]-C Allele Gene.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27396407
|abstract=Several genome-wide association studies have found that the rs11136000 polymorphism of the C allele ([[CLU]]-C) is associated with the risk for developing late-onset Alzheimer's disease (LOAD). However, the effects of the [[CLU]]-C/C genotype on brain structure, including gray and white matter, are not adequately understood. We aimed to clarify the gray matter and white matter integrity changes in non-demented ageing individuals with the AD risk gene of the rs11136000 polymorphism of the C allele ([[CLU]]-C) and the correlation with cognitive performance. Voxel-based analysis was used to compare the differences in high-resolution structural T1 and diffusion tensor imaging data between 31 [[CLU]]-C/C and 15 non-[[CLU]]-C/C carriers in nondemented older adults. Compared to non-[[CLU]]-C/C carriers, [[CLU]]-C homozygotes showed a reduced gray matter concentration (GMC) in the left parahippocampal gyrus, right middle frontal and temporal middle gyri, increased GMC in the left middle frontal and right fusiform gyri and increased gray matter volume (GMV) in the left middle frontal gyrus (P < 0.001). Decreased fractional anisotropy (FA) in the sub-gyral white matter of the left external capsule and left anterior cingulate and increased FA in the sub-gyral white matter of the left temporal lobe were also found in [[CLU]]-C/C genotype carriers. Moreover, the FA value in the left external capsule correlated with several cognitive measures. Our findings provide further evidence for the [[CLU]] risk variant as a candidate gene for AD and may serve as a pre-clinical neuroimaging phenotype of late-onset AD.
|mesh-terms=* Aged
* Aging
* Alleles
* Clusterin
* Cognition Disorders
* Diffusion Tensor Imaging
* Female
* Genome-Wide Association Study
* Genotype
* Gray Matter
* Humans
* Imaging, Three-Dimensional
* Male
* Middle Aged
* Neuropsychological Tests
* Polymorphism, Single Nucleotide
* White Matter

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5112753
}}
{{medline-entry
|title=Hippocampal proteomics defines pathways associated with memory decline and resilience in normal aging and Alzheimer's disease mouse models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27265785
|abstract=Alzheimer's disease (AD), the most common form of dementia in the elderly, has no cure. Thus, the identification of key molecular mediators of cognitive decline in AD remains a top priority. As aging is the most significant risk factor for AD, the goal of this study was to identify altered proteins and pathways associated with the development of normal aging and AD memory deficits, and identify unique proteins and pathways that may contribute to AD-specific symptoms. We used contextual fear conditioning to diagnose 8-month-old 5XFAD and non-transgenic (Ntg) mice as having either intact or impaired memory, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify hippocampal membrane proteins across groups. Subsequent analysis detected 113 proteins differentially expressed relative to memory status (intact vs impaired) in Ntg mice and 103 proteins in 5XFAD mice. Thirty-six proteins, including several involved in neuronal excitability and synaptic plasticity (e.g., [[GRIA1]], [[GRM3]], and SYN1), were altered in both normal aging and AD. Pathway analysis highlighted [[HDAC4]] as a regulator of observed protein changes in both genotypes and identified the [[REST]] epigenetic regulatory pathway and G  intracellular signaling as AD-specific pathways involved in regulating the onset of memory deficits. Comparing the hippocampal membrane proteome of Ntg versus AD, regardless of cognitive status, identified 138 differentially expressed proteins, including confirmatory proteins [[APOE]] and [[CLU]]. Overall, we provide a novel list of putative targets and pathways with therapeutic potential, including a set of proteins associated with cognitive status in normal aging mice or gene mutations that cause AD.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Chromatography, Liquid
* Conditioning, Psychological
* Disease Models, Animal
* Fear
* Hippocampus
* Humans
* Memory
* Memory Disorders
* Mice, Transgenic
* Presenilin-1
* Proteome
* Proteomics
* Psychological Tests
* Resilience, Psychological
* Tandem Mass Spectrometry
|keywords=* Aging
* Alzheimer’s disease
* Cognition
* Ion channels
* Proteomics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5135662
}}
{{medline-entry
|title=Risk-reducing Apolipoprotein E and Clusterin genotypes protect against the consequences of poor vascular health on executive function performance and change in nondemented older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27143425
|abstract=We examined independent and cumulative effects of 2 Alzheimer's-related genetic polymorphisms, Apolipoprotein E ([[APOE]]) and Clusterin ([[CLU]]), in relation to the deleterious effects of poor vascular health (pulse pressure [PP]) on executive function (EF) performance and change in nondemented older adults. Using a sample (n = 593; age range = 53-95 years) from the Victoria Longitudinal Study, we applied latent growth modeling to test the effect of PP, as moderated by [[APOE]] and [[CLU]], on an EF latent variable. EF was affected by higher levels of PP but differentially less so for carriers of low-risk alleles ([[APOE]] ɛ2 ; [[CLU]] TT) than for moderate- or high-risk alleles ([[APOE]] ɛ2-; [[CLU]] C ). The cumulative genetic risk of [[APOE]] plus [[CLU]] provided similar moderation of PP level effects on EF. Future research may focus on how [[APOE]] and [[CLU]] might provide different but complementary contributions to predicting EF level and change. Vascular health risk in synergistic association with risk-related polymorphisms can elucidate the neurobiological underpinnings of cognitive trajectories in nondemented aging.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alleles
* Apolipoproteins E
* Blood Pressure
* Clusterin
* Executive Function
* Female
* Genotype
* Humans
* Longitudinal Studies
* Male
* Middle Aged
* Risk
|keywords=* Apolipoprotein E
* Clusterin
* Executive function
* Pulse pressure
* Victoria Longitudinal Study
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4857019
}}
{{medline-entry
|title=Impact of [[PICALM]] and [[CLU]] on hippocampal degeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27017968
|abstract=[[PICALM]] and [[CLU]] are two major risk genes of late-onset Alzheimer's disease (LOAD), and there is strong molecular evidence suggesting their interaction on amyloid-beta deposition, hence finding functional dependency between their risk genotypes may lead to better understanding of their roles in LOAD development and greater clinical utility. In this study, we mainly investigated interaction effects of risk loci [[PICALM]] rs3581179 and [[CLU]] rs11136000 on hippocampal degeneration in both young and elderly adults in order to understand their neural mechanism on aging process, which may help identify robust biomarkers for early diagnosis and intervention. Besides volume we also assessed hippocampal shape phenotypes derived from diffeomorphic metric mapping and nonlinear dimensionality reduction. In elderly individuals (75.6 ± 6.7 years) significant interaction effects existed on hippocampal volume (P < 0.001), whereas in young healthy adults (19.4 ± 1.1 years) such effects existed on a shape phenotype (P = 0.01) indicating significant variation at hippocampal head and tail that mirror most AD vulnerable regions. Voxel-wise analysis also pointed to the same regions but lacked statistical power. In both cohorts, [[PICALM]] protective genotype AA only exhibited protective effects on hippocampal degeneration and cognitive performance when combined with [[CLU]] protective T allele, but adverse effects with [[CLU]] risk CC. This study revealed novel [[PICALM]] and [[CLU]] interaction effects on hippocampal degeneration along aging, and validated effectiveness of diffeomorphometry in imaging genetics study. Hum Brain Mapp 37:2419-2430, 2016. © 2016 Wiley Periodicals, Inc.
|mesh-terms=* Adolescent
* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Clusterin
* Cohort Studies
* Female
* Genetic Association Studies
* Genetic Load
* Genetic Predisposition to Disease
* Genotyping Techniques
* Hippocampus
* Humans
* Image Processing, Computer-Assisted
* Male
* Middle Aged
* Monomeric Clathrin Assembly Proteins
* Organ Size
* Phenotype
* Young Adult
|keywords=* Alzheimer's disease
* CLU
* PICALM
* hippocampus
* interaction
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867347
}}
{{medline-entry
|title=Gene-based aggregate SNP associations between candidate AD genes and cognitive decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/27005436
|abstract=Single nucleotide polymorphisms (SNPs) in and near [[ABCA7]], [[BIN1]], [[CASS4]], [[CD2AP]], [[CD33]], [[CELF1]], [[CLU]], complement receptor 1 ([[CR1]]), [[EPHA1]], [[EXOC3L2]], [[FERMT2]], HLA cluster (DRB5-DQA), [[INPP5D]], [[MEF2C]], MS4A cluster (MS4A3-[[MS4A6E]]), [[NME8]], [[PICALM]], [[PTK2B]], [[SLC24A4]], [[SORL1]], and [[ZCWPW1]] have been associated with Alzheimer's disease (AD) in large meta-analyses. We aimed to determine whether established AD-associated genes are associated with longitudinal cognitive decline by examining aggregate variation across these gene regions. In two single-sex cohorts of older, community-dwelling adults, we examined the association between SNPs in previously implicated gene regions and cognitive decline (age-adjusted person-specific cognitive slopes) using a Sequence Kernel Association Test (SKAT). In regions which showed aggregate significance, we examined the univariate association between individual SNPs in the region and cognitive decline. Only two of the original AD-associated SNPs were significantly associated with cognitive decline in our cohorts. We identified significant aggregate-level associations between cognitive decline and the gene regions [[BIN1]], [[CD33]], [[CELF1]], [[CR1]], HLA cluster, and [[MEF2C]] in the all-female cohort and significant associations with [[ABCA7]], HLA cluster, [[MS4A6E]], [[PICALM]], [[PTK2B]], [[SLC24A4]], and [[SORL1]] in the all-male cohort. We also identified a block of eight correlated SNPs in [[CD33]] and several blocks of correlated SNPs in [[CELF1]] that were significantly associated with cognitive decline in univariate analysis in the all-female cohort. 
|mesh-terms=* Aged
* Aging
* Alzheimer Disease
* Cognition Disorders
* DNA
* Female
* Genetic Association Studies
* Genetic Predisposition to Disease
* Humans
* Male
* Polymorphism, Single Nucleotide
|keywords=* Candidate AD genes
* Cognitive decline
* SNP associations
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005889
}}
{{medline-entry
|title=Apolipoprotein E and Clusterin can magnify effects of personality vulnerability on declarative memory performance in non-demented older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26343804
|abstract=Recent research has linked psychological (personality) factors and specific genetic risk polymorphisms to performance on neurocognitive phenotypes. We examined whether episodic or semantic memory performance is associated with (a) three personality traits (i.e. neuroticism, extraversion, and openness to experience), (b) two neurodegenerative-related polymorphisms (i.e. Apolipoprotein E ([[APOE]]; rs7412; rs429358), Clusterin ([[CLU]]; rs11136000)), and (c) cross-domain risk interactions (magnification effects). Linear growth models were examined to test independent associations between personality traits and declarative memory performance, and potential interaction effects with [[APOE]] and [[CLU]] genetic risk. Normal older adults (n = 282) with personality and genetic data from the Victoria Longitudinal Study were included at baseline and for up to 14 years of follow-up. First, we observed that higher openness to experience levels were associated with better episodic and semantic memory. Second, three significant gene × personality interactions were associated with poorer memory performance at baseline. These synergistic effects are: (a) [[APOE]] allelic risk (ε4 ) carriers with lower openness to experience levels, (b) [[CLU]] (no risk: T/T) homozygotes with higher extraversion levels, and (c) [[CLU]] (no risk: T/T) homozygotes with lower neuroticism levels. Specific neurodegenerative-related genetic polymorphisms (i.e. [[APOE]] and [[CLU]]) moderate and magnify the risk contributed by selected personality trait levels (i.e. openness to experience, extraversion) on declarative memory performance in non-demented aging. Future research could target interactions of other personality traits and genetic polymorphisms in different clinical populations to predict other neurocognitive deficits or transitions to cognitive impairment and dementia.
|mesh-terms=* Adult
* Aged
* Aging
* Anxiety Disorders
* Apolipoproteins E
* Clusterin
* Extraversion, Psychological
* Female
* Humans
* Linear Models
* Longitudinal Studies
* Male
* Memory
* Memory, Episodic
* Middle Aged
* Neurodegenerative Diseases
* Neuropsychological Tests
* Neuroticism
* Personality
* Polymorphism, Genetic
* Risk Factors
|keywords=* Apolipoprotein E
* Clusterin
* Victoria Longitudinal Study
* genetic risk
* memory
* personality traits
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826141
}}
{{medline-entry
|title=Combined effects of Alzheimer risk variants in the [[CLU]] and ApoE genes on ventricular expansion patterns in the elderly.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24806679
|abstract=The C allele at the rs11136000 locus in the clusterin ([[CLU]]) gene is the third strongest known genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent genome-wide association study of LOAD found the strongest evidence of association with [[CLU]] at rs1532278, in high linkage disequilibrium with rs11136000. Brain structure and function are related to the [[CLU]] risk alleles, not just in LOAD patients but also in healthy young adults. We tracked the volume of the lateral ventricles across baseline, 1-year, and 2-year follow-up scans in a large sample of elderly human participants (N = 736 at baseline), from the Alzheimer's Disease Neuroimaging Initiative, to determine whether these [[CLU]] risk variants predicted longitudinal ventricular expansion. The rs11136000 major C allele-previously linked with reduced [[CLU]] expression and with increased risk for dementia-predicted faster expansion, independently of dementia status or ApoE genotype. Further analyses revealed that the [[CLU]] and ApoE risk variants had combined effects on both volumetric expansion and lateral ventricle surface morphology. The rs1532278 locus strongly resembles a regulatory element. Its association with ventricular expansion was slightly stronger than that of rs11136000 in our analyses, suggesting that it may be closer to a functional variant. Clusterin affects inflammation, immune responses, and amyloid clearance, which in turn may result in neurodegeneration. Pharmaceutical agents such as valproate, which counteract the effects of genetically determined reduced clusterin expression, may help to achieve neuroprotection and contribute to the prevention of dementia, especially in carriers of these [[CLU]] risk variants. 
|mesh-terms=* Aged
* Aging
* Alleles
* Alzheimer Disease
* Apolipoproteins E
* Brain Mapping
* Clusterin
* DNA
* Female
* Genome-Wide Association Study
* Genotype
* Humans
* Image Processing, Computer-Assisted
* Lateral Ventricles
* Magnetic Resonance Imaging
* Male
* Real-Time Polymerase Chain Reaction
* Regression Analysis
* Risk
|keywords=* ApoE
* brain aging
* clusterin
* genetics
* neuroimaging
* ventricular expansion
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4012312
}}
{{medline-entry
|title=The benefits of staying active in old age: physical activity counteracts the negative influence of [[PICALM]], [[BIN1]], and [[CLU]] risk alleles on episodic memory functioning.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24660791
|abstract=[[PICALM]], [[BIN1]], [[CLU]], and [[APOE]] are top candidate genes for Alzheimer's disease, and they influence episodic memory performance in old age. Physical activity, however, has been shown to protect against age-related decline and counteract genetic influences on cognition. The aims of this study were to assess whether (a) a genetic risk constellation of [[PICALM]], [[BIN1]], and [[CLU]] polymorphisms influences cognitive performance in old age; and (b) if physical activity moderates this effect. Data from the SNAC-K population-based study were used, including 2,480 individuals (age range = 60 to 100 years) free of dementia at baseline and at 3- to 6-year follow-ups. Tasks assessing episodic memory, perceptual speed, knowledge, and verbal fluency were administered. Physical activity was measured using self-reports. Individuals who had engaged in frequent health- or fitness-enhancing activities within the past year were compared with those who were inactive. Genetic risk scores were computed based on an integration of risk alleles for [[PICALM]] (rs3851179 G allele, rs541458 T allele), [[BIN1]] (rs744373 G allele), and [[CLU]] (rs11136000 T allele). High genetic risk was associated with reduced episodic memory performance, controlling for age, education, vascular risk factors, chronic diseases, activities of daily living, and [[APOE]] gene status. Critically, physical activity attenuated the effects of genetic risk on episodic memory. Our findings suggest that participants with high genetic risk who maintain a physically active lifestyle show selective benefits in episodic memory performance.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aged
* Aged, 80 and over
* Aging
* Alleles
* Alzheimer Disease
* Clusterin
* Cognition
* Exercise
* Female
* Genetic Predisposition to Disease
* Humans
* Male
* Memory, Episodic
* Middle Aged
* Monomeric Clathrin Assembly Proteins
* Nuclear Proteins
* Risk Factors
* Sweden
* Tumor Suppressor Proteins

|full-text-url=https://sci-hub.do/10.1037/a0035465
}}
{{medline-entry
|title=Age-dependent effect of Alzheimer's risk variant of [[CLU]] on EEG alpha rhythm in non-demented adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24379779
|abstract=Polymorphism in the genomic region harboring the [[CLU]] gene (rs11136000) has been associated with the risk for Alzheimer's disease (AD). [[CLU]] C allele is assumed to confer risk for AD and the allele T may have a protective effect. We investigated the influence of the AD-associated [[CLU]] genotype on a common neurophysiological trait of brain activity (resting-state alpha-rhythm activity) in non-demented adults and elucidated whether this influence is modified over the course of aging. We examined quantitative electroencephalography (EEG) in a cohort of non-demented individuals (age range 20-80) divided into young (age range 20-50) and old (age range 51-80) cohorts and stratified by [[CLU]] polymorphism. To rule out the effect of the apolipoprotein E (ApoE) genotype on EEG characteristics, only subjects without the ApoE ε4 allele were included in the study. The homozygous presence of the AD risk variant [[CLU]] CC in non-demented subjects was associated with an increase of alpha3 absolute power. Moreover, the influence of [[CLU]] genotype on alpha3 was found to be higher in the subjects older than 50 years of age. The study also showed age-dependent alterations of alpha topographic distribution that occur independently of the [[CLU]] genotype. The increase of upper alpha power has been associated with hippocampal atrophy in patients with mild cognitive impairment (Moretti etal., 2012a). In our study, the [[CLU]] CC-dependent increase in upper alpha rhythm, particularly enhanced in elderly non-demented individuals, may imply that the genotype is related to preclinical dysregulation of hippocampal neurophysiology in aging and that this factor may contribute to the pathogenesis of AD. 

|keywords=* Alzheimer’s disease
* EEG
* aging
* alpha rhythm
* clusterin
* genetic predisposition
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3861782
}}
{{medline-entry
|title=[[CLU]] genetic variants and cognitive decline among elderly and oldest old.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/24244428
|abstract=The [[CLU]] gene is one of the prime genetic candidates associated with Alzheimers disease. In the present study [[CLU]] genotypes and haplotypes were associated with baseline cognition and the rate of cognitive decline in two cohorts, the Danish 1905 birth cohort (93 years of age in 1998) and the Longitudinal Study of Aging Danish twins (LSADT) (73-83 year old twins in 1997). Both Mini Mental State Examination (MMSE) and a cognitive composite score was attained up to six times for up to 10 years and analysed using random effects models and vital status. The rs11136000 T allele was associated with better baseline cognitive performance both in the LSADT (effect on intercept: 0.41 95% CI [-0.04; 0.87]) and the 1905 birth cohort (effect on intercept: 0.28 95% CI [0.01; 0.55]), although it did not reach significance in the LSADT cohort. However, the rs11136000 T allele was significantly associated with a steeper decline (effect on slope: -0.06 95% CI [-0.11; -0.01]) in the LSADT cohort, but not in the 1905 birth cohort. Haplotype analyses revealed that carriers of the common rs11136000, rs1532278 and rs9331888 TTC haplotype (36%) in the [[CLU]] gene performed cognitively better than non-carriers in the 1905 birth cohort (effect on intercept: 0.50 95% CI [0.12; 0.91]) and carriers of a rare TCC haplotype (1%) performed worse on the cognitive composite score (effect on intercept: -1.51 95% CI [-2.92; -0.06]). The association between the TTC haplotype and better cognitive composite score was higher among those surviving past the age of 98 (p = 0.014), and among these the TTC haplotype was borderline associated with a steep decline (effect on slope: -0.13 95% CI [-0.27; 0.00]). In summery [[CLU]] genetic variants associate with cognition in two cohorts, but the genetic effect of [[CLU]] seems to regress toward the mean when aging. 
|mesh-terms=* Aged
* Aging
* Alleles
* Clusterin
* Cognition
* Cognition Disorders
* Female
* Follow-Up Studies
* Haplotypes
* Humans
* Male
* Polymorphism, Single Nucleotide

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828341
}}
{{medline-entry
|title=The molecular chaperone apolipoprotein J/clusterin as a sensor of oxidative stress: implications in therapeutic approaches - a mini-review.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/23689375
|abstract=Organisms are constantly exposed to physiological and environmental stresses and therefore require an efficient surveillance of genome and proteome quality in order to prevent disruption of homeostasis. Central to the intra- and extracellular proteome surveillance system are the molecular chaperones that contribute to both proteome maintenance and clearance. The conventional protein product of the apolipoprotein J/clusterin ([[CLU]]) gene is a heterodimeric secreted glycoprotein (also termed as s[[CLU]]) with a ubiquitous expression in human tissues. [[CLU]] exerts a small heat shock protein-like stress-induced chaperone activity and has been functionally implicated in numerous physiological processes as well as in ageing and most age-related diseases including tumorigenesis, neurodegeneration, and cardiovascular and metabolic syndromes. The [[CLU]] gene is differentially regulated by a wide variety of stimuli due to the combined presence of many distinct regulatory elements in its promoter that make it an extremely sensitive cellular biosensor of environmental and/or oxidative stress. Downstream to [[CLU]] gene induction, the [[CLU]] protein seems to actively intervene in pathological states of increased oxidative injury due to its chaperone-related property to inhibit protein aggregation and precipitation (a main feature of oxidant injury), as well as due to its reported distribution in both extra- and, most likely, intracellular compartments. On the basis of these findings, [[CLU]] has emerged as a unique regulator of cellular proteostasis. Nevertheless, it seemingly exerts a dual function in pathology. For instance, in normal cells and during early phases of carcinogenesis, [[CLU]] may inhibit tumor progression as it contributes to suppression of proteotoxic stress. In advanced neoplasia, however, it may offer a significant survival advantage in the tumor by suppressing many therapeutic stressors and enhancing metastasis. This review will critically present a synopsis of recent novel findings that relate to the function of this amazing molecule and support the notion that [[CLU]] is a biosensor of oxidative injury; a common link between ageing and all pathologies where [[CLU]] has been implicated. Potential future perspectives, implications and opportunities for translational research and the development of new therapies will be discussed.
|mesh-terms=* Aging
* Animals
* Clusterin
* Gene Expression Regulation
* Humans
* Neoplasms
* Oxidative Stress
* Protein Isoforms
* Proteome

|full-text-url=https://sci-hub.do/10.1159/000351207
}}