Genetic association of low density lipoprotein receptor and Alzheimer's disease

Gopalraj, Rangaraj; Zhu, Haiyan; Kelly, Jeremiah F.; Mendiondo, Marta S.; Pulliam, Joseph F.; Bennett, David A.; Estus, Steven

doi:10.1016/j.neurobiolaging.2004.09.001

Cited by 46 publications

(33 citation statements)

References 25 publications

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“…The results of our study (OR ¼ 0.92; 95% CI ¼ 0.43-1.96; P ¼ 0.84) fail to confirm the findings of Cheng et al [2005] that double homozygosity for LDLR exon 8 allele G and LDLR exon 13 allele C among APOE e4 allele carriers increases risk of AD. We did not confirm (OR ¼ 1.32; 95% CI ¼ 0.83-2.09; P ¼ 0.24) the results of Gopalraj et al [2005] that homozygosity for LDLR exon 10 allele G is associated with AD. All three LDLR polymorphisms were in significant linkage disequilibrium with each other (P < 0.0001), both in patients and controls.…”

Section: Resultscontrasting

confidence: 69%

“…Polymorphisms in multiple genes that participate in cholesterol metabolism are associated with changes in the risk of AD. The APOE e4 allele is the most important and well-established association [Poirier, 2003], but genetic variation in exons 8, 10, 13, and 15 of LDLR has also been proposed to modify the risk of AD [Cheng et al, 2005;Gopalraj et al, 2005]. In contrast, in other studies no correlation was observed between polymorphisms in LDLR gene and AD [Lendon et al, 1997;Retz et al, 2001].…”

Section: Introductionmentioning

confidence: 99%

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No association between low density lipoprotein receptor genetic variants and Alzheimer's disease risk

Rodríguez¹,

Mateo²,

Llorca³

et al. 2006

American J of Med Genetics Pt B

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A number of studies suggest that brain cholesterol metabolism may play a role in Alzheimer's disease (AD) development, probably through modulation of amyloid beta production. The discovery that apolipoprotein E (APOE) epsilon4 allele is a risk factor for sporadic AD raises the possibility that the receptors to which APOE binds on the surface of neurons are also involved in the neurodegenerative process. To evaluate the relationship between low density lipoprotein receptor (LDLR) genetic variant and AD, independently or in concert with the APOE epsilon4 allele, we examined three LDLR polymorphisms located in exons 8 (rs 11669576), 10 (rs 5930), and 13 (rs 5925), in a large group of 322 Spanish AD patients and 314 controls. The current study does not demonstrate an association between LDLR genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE epsilon4 allele.

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Section: Resultscontrasting

confidence: 69%

Section: Introductionmentioning

confidence: 99%

No association between low density lipoprotein receptor genetic variants and Alzheimer's disease risk

Rodríguez¹,

Mateo²,

Llorca³

et al. 2006

American J of Med Genetics Pt B

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“…Although miR-128 transfection decreased the association of many mRNAs with the AGO-miRNP, there were some apparent miR-128 targets. mRNAs that were incorporated consistently into the miRNP after miR-128 transfections included intriguing Ohkuma et al 2001;Yamawaki et al 2003;Gopalraj et al 2005). …”

Section: Discussionmentioning

confidence: 99%

Anti-Argonaute RIP-Chip shows that miRNA transfections alter global patterns of mRNA recruitment to microribonucleoprotein complexes

Wang

Wilfred²,

Hu³

et al. 2009

RNA

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MicroRNAs (miRNAs) play key roles in gene expression regulation by guiding Argonaute (AGO)-containing microribonucleoprotein (miRNP) effector complexes to target polynucleotides. There are still uncertainties about how miRNAs interact with mRNAs. Here we employed a biochemical approach to isolate AGO-containing miRNPs from human H4 tumor cells by coimmunoprecipitation (co-IP) with a previously described anti-AGO antibody. Co-immunoprecipitated (co-IPed) RNAs were subjected to downstream Affymetrix Human Gene 1.0 ST microarray analysis. During rigorous validation, the ''RIP-Chip'' assay identified target mRNAs specifically associated with AGO complexes. RIP-Chip was performed after transfecting brain-enriched miRNAs (miR-107, miR-124, miR-128, and miR-320) and nonphysiologic control miRNA to identify miRNA targets. As expected, the miRNA transfections altered the mRNA content of the miRNPs. Specific mRNA species recruited to miRNPs after miRNA transfections were moderately in agreement with computational target predictions. In addition to recruiting mRNA targets into miRNPs, miR-107 and to a lesser extent miR-128, but not miR-124 or miR-320, caused apparent exclusion of some mRNAs that are normally associated with miRNPs. MiR-107 and miR-128 transfections also result in decreased AGO mRNA and protein levels. However, AGO mRNAs were not recruited to miRNPs after either miR-107 or miR-128 transfection, confirming that miRNAs may alter gene expression without stable association between particular mRNAs and miRNPs. In summary, RIPChip assays constitute an optimized, validated, direct, and high-throughput biochemical assay that provides data about specific miRNA:mRNA interactions, as well as global patterns of regulation by miRNAs.

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“…The A allele of rs11669576 has been associated with variable risk of AD, either increasing risk when in combination with copies of APOE-e4 7 or decreasing risk -only in women -when in combination with other LDLR polymorphisms, 36 while the A allele of rs5930 was associated with lower risk of AD when combined with other LDLR polymorphisms in an earlier study. 13 Although neuropsychiatric symptoms have not previously been studied in association with variants of LDLR, genotypes associated with less AD neuropathology 36 could lead to later dementia onset and milder behavioral burden in earlier stages.…”

Section: 019mentioning

confidence: 99%

“…The two functional variants of the angiotensin-converting enzyme gene (ACE) with the most significant effects for higher activity and boosted serum levels of the angiotensinconverting enzyme (ACE) are the promoter polymorphisms rs1800764 and rs4291, affecting risk and age at onset of the amnestic phenotype of AD, 11 as well as cognitive decline and incidence of early-onset hypertension. 12 The LDLR mediates increased astrocytic expression of APOE induced by amyloid-b, 4 whereas storage and release of cholesterol depend on the expression of the low-density lipoprotein receptor gene (LDLR), which resides within a region linked to AD in 19p13.3; rs11669576 7 and rs5930 13 are two of the most important genetic variants of the epidermal growth factor precursor homology domain of LDLR to be associated with disrupted cholesterol metabolism and variability in the risk of AD. Cholesterol governs synaptogenesis and myelin biosynthesis, 14 while the cholesteryl ester transfer protein (CETP) is associated with reverse cholesterol transport (from tissues to the liver) 5 ; protective cholesteryl ester transfer protein gene (CETP) variants lead to lower serum CETP levels and healthier lipid profiles, 15 though not all studies have shown genetically mediated lifetime cognitive effects.…”

Section: Introductionmentioning

confidence: 99%

Associations of cerebrovascular metabolism genotypes with neuropsychiatric symptoms and age at onset of Alzheimer’s disease dementia

Oliveira

Chen

Smith

et al. 2017

Rev. Bras. Psiquiatr.

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Objective: To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer's disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. Methods: Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121. Results: Considering 201 patients, only APOE-e4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior. Conclusion: Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD.

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Genetic association of low density lipoprotein receptor and Alzheimer's disease

Cited by 46 publications

References 25 publications

No association between low density lipoprotein receptor genetic variants and Alzheimer's disease risk

No association between low density lipoprotein receptor genetic variants and Alzheimer's disease risk

Anti-Argonaute RIP-Chip shows that miRNA transfections alter global patterns of mRNA recruitment to microribonucleoprotein complexes

Associations of cerebrovascular metabolism genotypes with neuropsychiatric symptoms and age at onset of Alzheimer’s disease dementia

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