scholarly journals Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU

2020 ◽  
Vol 21 (19) ◽  
pp. 7079
Author(s):  
Seonggyun Han ◽  
Kwangsik Nho ◽  
Younghee Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alternative Splicing ◽  
Genetic Variants ◽  
Temporal Cortex ◽  
Integrative Approach ◽  
Splicing Regulation ◽  
Rna Seq ◽  
Risk Variant

Clusterin (CLU) is one of the risk genes most associated with late onset Alzheimer’s disease (AD), and several genetic variants in CLU are associated with AD risk. However, the functional role of known AD risk genetic variants in CLU has been little explored. We investigated the effect of an AD risk variant (rs7982) in the 5th exon of CLU on alternative splicing by using an integrative approach of brain-tissue-based RNA-Seq and whole genome sequencing data from Accelerating Medicines Partnership—Alzheimer’s Disease (AMP-AD). RNA-Seq data were generated from three regions in the temporal lobe of the brain—the temporal cortex, superior temporal gyrus, and parahippocampal gyrus. The rs7982 was significantly associated with intron retention (IR) of the 5th exon of CLU; as the number of alternative alleles (G) increased, the IR rates decreased more significantly in females than in males. Our results suggest a sex-dependent role of rs7982 in AD pathogenesis via splicing regulation.

scholarly journals Genetic Variants of Lipoprotein Lipase and Regulatory Factors Associated with Alzheimer’s Disease Risk

2020 ◽  
Vol 21 (21) ◽  
pp. 8338
Author(s):  
Kimberley D. Bruce ◽  
Maoping Tang ◽  
Philip Reigan ◽  
Robert H. Eckel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipoprotein Lipase ◽  
Genetic Variants ◽  
Disease Risk ◽  
Lipoprotein Metabolism ◽  
Protective Role ◽  
Direct Role ◽  
The Brain

Lipoprotein lipase (LPL) is a key enzyme in lipid and lipoprotein metabolism. The canonical role of LPL involves the hydrolysis of triglyceride-rich lipoproteins for the provision of FFAs to metabolic tissues. However, LPL may also contribute to lipoprotein uptake by acting as a molecular bridge between lipoproteins and cell surface receptors. Recent studies have shown that LPL is abundantly expressed in the brain and predominantly expressed in the macrophages and microglia of the human and murine brain. Moreover, recent findings suggest that LPL plays a direct role in microglial function, metabolism, and phagocytosis of extracellular factors such as amyloid- beta (Aβ). Although the precise function of LPL in the brain remains to be determined, several studies have implicated LPL variants in Alzheimer’s disease (AD) risk. For example, while mutations shown to have a deleterious effect on LPL function and expression (e.g., N291S, HindIII, and PvuII) have been associated with increased AD risk, a mutation associated with increased bridging function (S447X) may be protective against AD. Recent studies have also shown that genetic variants in endogenous LPL activators (ApoC-II) and inhibitors (ApoC-III) can increase and decrease AD risk, respectively, consistent with the notion that LPL may play a protective role in AD pathogenesis. Here, we review recent advances in our understanding of LPL structure and function, which largely point to a protective role of functional LPL in AD neuropathogenesis.

scholarly journals Association Study of Genetic Variants inCDKN2A/CDKN2BGenes/Loci with Late-Onset Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-4
Author(s):  
Andrea Tedde ◽  
Irene Piaceri ◽  
Silvia Bagnoli ◽  
Ersilia Lucenteforte ◽  
Uwe Ueberham ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Genetic Variant ◽  
Case Control Study ◽  
Late Onset ◽  
Common Genetic Variant ◽  
Genome Wide ◽  
Control Study

Alzheimer's disease (AD) is the most common form of dementia clinically characterized by progressive impairment of memory and other cognitive functions. Many genetic researches in AD identified one common genetic variant (ε4) in Apolipoprotein E (APOE) gene as a risk factor for the disease. Two independent genome-wide studies demonstrated a new locus on chromosome 9p21.3 implicated in Late-Onset Alzheimer's Disease (LOAD) susceptibility in Caucasians. In the present study, we investigated the role of three SNP's in theCDKN2Agene (rs15515, rs3731246, and rs3731211) and one in theCDKN2Bgene (rs598664) located in 9p21.3 using an association case-control study carried out in a group of Caucasian subjects including 238 LOAD cases and 250 controls. The role ofCDKN2AandCDKN2Bgenetic variants in AD is not confirmed in our LOAD patients, and further studies are needed to elucidate the role of these genes in the susceptibility of AD.

scholarly journals RNA-Seq analysis in mutant zebrafish reveals role of U1C protein in alternative splicing regulation

2011 ◽  
Vol 30 (10) ◽  
pp. 1965-1976 ◽  
Author(s):  
Tanja Dorothe Rösel ◽  
Lee-Hsueh Hung ◽  
Jan Medenbach ◽  
Katrin Donde ◽  
Stefan Starke ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Splicing Regulation ◽  
Rna Seq

Explore the role of CR1 genetic variants in late-onset Alzheimer’s disease susceptibility

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Liu Lu ◽  
Qing-yu Yao ◽  
Sha-Sha Ruan ◽  
Jia-Wei Hu ◽  
Wen-jun Long ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Disease Susceptibility ◽  
Late Onset

scholarly journals Ezrin Expression is Increased During Disease Progression in a Tauopathy Mouse Model and Alzheimer’s Disease

2018 ◽  
Vol 15 (12) ◽  
pp. 1086-1095 ◽  
Author(s):  
Irving E. Vega ◽  
Andrew Umstead ◽  
Cassandra M. Wygant ◽  
John S. Beck ◽  
Scott E. Counts
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Stress Responses ◽  
Temporal Cortex ◽  
Motor Impairment ◽  
Diagnostic Tools ◽  
Protein Abundance ◽  
Ezrin Expression

Background: The lack of diagnostic tools and disease-modifying treatments against Alzheimer’s disease (AD) and related disorders, collectively known as tauopathies, has led to a socioeconomic burden of epidemic proportion. Proteomics approaches can be used to identify novel proteome changes that could help us understand the pathogenesis of tau-related pathological hallmarks and/or cellular stress responses associated with tauopathy. These studies, however, need to be conducted taking into consideration brain region specificity and stage of neurodegeneration in order to provide insights about the pathological role of the identified proteins. Methods: We used a tauopathy mouse model (JNPL3) that expresses human tau bearing a P301L mutation and develops motor impairment, the severity of which correlates with the increased accumulation of pathological tau. Tissue was dissected from asymptomatic and severely motor impaired JNPL3 mice as well as non-transgenic littermate controls and subjected to two-dimensional gel electrophoresis. Differentially abundant protein spots were identified by tandem mass spectrometry. Postmortem mild cognitive impairment (MCI), AD and normal aging controls were used to validate the pathological significance of the identified protein. Results: Ezrin was identified as a protein that is upregulated in tau-mediated neurodegeneration. We demonstrate that Ezrin protein abundance increased in JNPL3 mice preceded motor impairment and was sustained in severely motor impaired mice. Ezrin expression was also increased in the temporal cortex of MCI and AD patients. Conclusion: The results demonstrate that increased Ezrin protein abundance changes are associated with the early stages of neurodegeneration in tauopathy models and human disease. Understanding the role of Ezrin in tauopathies such as AD may provide new insights for targeting tau-mediated neurodegeneration.

scholarly journals Validation of a priori candidate Alzheimer’s disease SNPs with brain amyloid-beta deposition

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Michael Vacher ◽  
Tenielle Porter ◽  
Victor L. Villemagne ◽  
Lidija Milicic ◽  
Madeline Peretti ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
A Priori ◽  
Imaging Biomarker ◽  
Evidence Based ◽  
Potential Implication ◽  
Functional Studies ◽  
Brain Amyloid Deposition

AbstractThe accumulation of brain amyloid β (Aβ) is one of the main pathological hallmarks of Alzheimer’s disease (AD). However, the role of brain amyloid deposition in the development of AD and the genetic variants associated with this process remain unclear. In this study, we sought to identify associations between Aβ deposition and an a priori evidence based set of 1610 genetic markers, genotyped from 505 unrelated individuals (258 Aβ+ and 247 Aβ−) enrolled in the Australian Imaging, Biomarker & Lifestyle (AIBL) study. We found statistically significant associations for 6 markers located within intronic regions of 6 genes, including AC103796.1-BDNF, PPP3R1, NGFR, KL, ABCA7 & CALHM1. Although functional studies are required to elucidate the role of these genes in the accumulation of Aβ and their potential implication in AD pathophysiology, our findings are consistent with results obtained in previous GWAS efforts.

The glutathione S-transferase polymorphisms in a control population and in Alzheimer's disease patients

2004 ◽  
Vol 42 (3) ◽  
Author(s):  
Irena Žuntar ◽  
Svjetlana Kalanj-Bognar ◽  
Elizabeta Topic ◽  
Roberta Petlevski ◽  
Mario Štefanović ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Fragment Length Polymorphism ◽  
Glutathione S Transferase ◽  
Chain Reaction ◽  
Increased Risk ◽  
Pcr Rflp ◽  
Polymerase Chain

AbstractIn this study, we investigated the role of glutathione S-transferase P1 (GSTP1) polymorphisms in the pathogenesis of Alzheimer's disease (AD). We genotyped the GSTP1 polymorphisms in exon 5 (A313G) and exon 6 (C341T) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 56 Croatian patients with AD and 231 controls. Distributions and frequencies of GSTP1 genetic variants were not statistically different between AD patients and healthy controls. Higher frequencies of the mutant genotypes were observed in AD patients (13% for both A313G and C341T) when compared with control subjects (7% for A313G and 8% for C341T), but association of GSTP1 GG (OR 2.057, 95% CI 0.796–5.315, p=0.094) and TT (OR 1.691, 95% CI 0.669–4.270, p=0.514) genotypes with an increased risk of AD was not confirmed by statistical analysis. The frequencies of

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