The genetics of Alzheimer&amp;#39;s disease

Bagyinszky, Eva; Youn, Young Chul; An, Seong Soo A.; Kim, SangYun

doi:10.2147/cia.s51571

Cited by 144 publications

(114 citation statements)

References 189 publications

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“…At the same time, two independent groups revealed TREM2 as a rare but significant risk for AD through exome sequencing (Guerreiro et al 2013;Jonsson et al 2013). Not surprisingly, several of these AD risk molecules are involved in immune and inflammatory process (Bagyinszky et al 2014). In this review, due to limitations of space, we mainly focus on these six genes: CR1, CLU, HLA-DRB5/DRB1, INPP5D, MEF2C, and TREM2.…”

Section: Molecular Geneticsmentioning

confidence: 99%

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Zhang

et al. 2015

Arch. Immunol. Ther. Exp.

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Alzheimer's disease (AD) is a complex agerelated neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE e4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.

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Section: Molecular Geneticsmentioning

confidence: 99%

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Zhang

et al. 2015

Arch. Immunol. Ther. Exp.

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“…26) In general, the steady state level of biological molecules is determined by a constant balance between anabolic and catabolic rates. Impairment of this metabolic balance leads to Aβ accumulation in the brain.…”

Section: Discussionmentioning

confidence: 99%

Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts

Kawakubo

Mori

Shirotani

et al. 2017

Biological & Pharmaceutical Bulletin

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Amyloid-β peptide (Aβ) accumulation is a triggering event leading to the Alzheimer's disease (AD) pathological cascade. Almost all familial AD-linked gene mutations increase Aβ production and accelerate the onset of AD. The Swedish mutation of amyloid precursor protein (APP) affects β-secretase activity and increases Aβ production up to ca. 6-fold in cultured cells; the onset age is around 50. Down syndrome (DS) patients with chromosome 21 trisomy present AD-like pathologies at earlier ages (40s) compared with sporadic AD patients, because APP gene expression is 1.5-fold higher than that in healthy people, thus causing a 1.5-fold increase in Aβ production. However, when comparing the causal relationship of Aβ accumulation with the onset age between the above two populations, early DS pathogenesis does not appear to be accounted for by the increased Aβ production alone. In this study, we found that neprilysin, a major Aβ-degrading enzyme, was downregulated in DS patient-derived fibroblasts, compared with healthy people-derived fibroblasts. Treatment with harmine, an inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), which is located in the DS critical region of chromosome 21, and gene knockdown of DYRK1A, upregulated neprilysin in fibroblasts. These results suggest that a decrease in the Aβ catabolic rate may be, at least in part, one of the causes for accelerated AD-like pathogenesis in DS patients if a similar event occurs in the brains, and that neprilysin activity may be regulated directly or indirectly by DYRK1A-mediated phosphorylation. DYRK1A inhibition may be a promising disease-modifying therapy for AD via neprilysin upregulation.Key words Alzheimer's disease; chromosome 21; down syndrome; dual-specificity tyrosine phosphorylationregulated kinase 1A; neprilysin Alzheimer's disease (AD) brains are pathologically characterized by numerous senile plaques and neurofibrillary tangles, which consist of aggregation amyloid-β peptide (Aβ) and hyperphosphorylated tau, respectively, and prominent neuronal cell death. Aβ is generated from amyloid precursor protein (APP) by β-and γ-secretase-mediated sequential cleavages, followed by Aβ degradation by neprilysin (NEP). Aβ in healthy brains is maintained at a constant level by an equilibrium between the production and degradation rates. 1)An imbalance arising by a subtle change in either rate leads to Aβ accumulation.The Swedish double mutation (K670N/M671L) in APP, one of the most well-known mutations in familial AD, leads to a dramatic increase in total Aβ production.2,3) The average onset age of Swedish familial AD is around 55 years.4) On the other hand, Down syndrome (DS) is one of the most frequently occurring chromosomal abnormalities. 5,6) Approximately 95% of DS is caused by standard trisomy 21, which is an extra copy of chromosome 21. The remaining causes, chromosomal translocation and mosaicism, account for 1-5 and 1-2% of DS cases, respectively. DS patients have unique physical characteristics and suffer from various comp...

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“…Given that the rs2075650 of TOMM40 is in strong linkage disequilibrium with rs429358 (C→T, Arg130Cys) of APOE, certain clinical implications may originate from APOE (27,32). Although the minor C allele of rs429358 of APOE was shown to be associated with the increased serum LDL-cholesterol level, as well as the increased risk of coronary artery disease and Alzheimer's disease (27,33,34), the association of this SNP with ischemic stroke has not been determined (35). The present study shows that rs2075650 of TOMM40 was associated with ischemic stroke with the minor G allele being protective against this condition, although the underlying molecular mechanism remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Association of TOMM40 and SLC22A4 polymorphisms with ischemic stroke

et al. 2015

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Abstract. Recent genome-wide association studies (GWASs) and their meta-analyses have identified various genes and loci underlying the predisposition to ischemic stroke or coronary artery disease in Caucasian populations. Given that ischemic stroke and coronary artery disease may have a shared genetic architecture, certain polymorphisms may confer genetic susceptibility to these two diseases. The aim of the present study was to examine the possible association of ischemic stroke with 29 single-nucleotide polymorphisms (SNPs) previously identified by the meta-analyses of GWASs as susceptibility loci for coronary artery disease. The study population comprised 3,187 Japanese individuals, including 894 subjects with ischemic stroke and 2,293 controls. The genotypes for the 29 SNPs of the 28 genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons of the allele frequencies by the χ 2 test between subjects with ischemic stroke and controls revealed that rs9319428 (G→A) of the fms-related tyrosine kinase 1 gene (P=0.0471), rs2075650 (G→A) of the translocase of outer mitochondrial membrane 40 homolog gene (TOMM40, P=0.0102) and rs273909 (T→C) of the solute carrier family 22, member 4 gene (SLC22A4, P=0.0097) were significantly (P<0.05) associated with the prevalence of ischemic stroke. Multivariable logistic regression analysis with adjustment for age, gender, body mass index, smoking status and the prevalence of hypertension, diabetes mellitus and dyslipidemia revealed that rs2075650 of TOMM40 (P=0.0443; recessive model; odds ratio=0.50) and rs273909 of SLC22A4 (P= 0.0123; dominant model; odds ratio= 0.45) were significantly associated with ischemic stroke with the minor G and C allele, respectively, being protective against this condition. TOMM40 and SLC22A4 may thus be susceptibility loci for ischemic stroke in Japanese individuals.

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The genetics of Alzheimer's disease

Cited by 144 publications

References 189 publications

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts

Association of TOMM40 and SLC22A4 polymorphisms with ischemic stroke

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