α2-Macroglobulin gene polymorphisms show racial diversity and are not associated with Alzheimerʼs disease

Higuchi, Susumu; Matsushita, Satoru; Nakane, Jun; Arai, Hiroyuki; Matsui, Toshifumi; Urakami, Katsuya; Yuzuriha, Takefumi; Takeda, Atsushi

doi:10.1097/00001756-200004270-00005

Cited by 20 publications

(10 citation statements)

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“…However, very little difference was detected in the distribution of both genotypes and alleles between our cases and control subjects. This is in agreement with other case control [Crawford et al, 1999;Wavrant-De Vrieze et al, 1999;Higuchi et al, 2000] and family-based studies Romas et al, 2000], although the association was con®rmed in a Finnish study [Myllykangas et al, 1999]. It seems clear, however, that if the A2M gene has a role in in¯uencing risk for AD, it is likely to be small and may only exist in certain de®ned populations.…”

Section: Discussionsupporting

confidence: 89%

See 1 more Smart Citation

Common polymorphisms in LRP and A2M do not affect genetic risk for Alzheimer disease in Northern Ireland

McIlroy¹,

Dynan²,

Vahidassr³

et al. 2001

Am. J. Med. Genet.

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Genetic variation in one of the major APOE receptors in the brain has been associated with increased risk for Alzheimer disease (AD). A C/T polymorphism in exon 3 and a tetranucleotide repeat polymorphism in the 5' region of the low-density lipoprotein receptor-related protein gene have been reported to increase risk in some studies but these reports have not been universally replicated. In addition, genetic variation in another ligand of LRP, alpha-2 macroglobulin (A2M), has also been associated with increased AD risk. However, these reports also remain controversial. We have genotyped both LRP polymorphisms and two polymorphisms in the A2M gene in a large group of clinically well-defined AD cases and controls from the relatively genetically homogeneous Northern Ireland population. Comparison of genotype and allele frequencies for polymorphisms in LRP revealed no significant differences between cases and controls. Multiple logistic regression analysis performed to assess any possible interaction between LRP and APOE revealed little evidence for genetic interaction despite the obvious biological interaction. Genotype and allele comparisons between the groups for the A2M polymorphisms also gave no evidence that either polymorphism increased risk for disease. The results from this study indicate that polymorphisms in LRP and A2M are not associated with increased risk for AD in Northern Ireland.

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Section: Discussionsupporting

confidence: 89%

“…However, studies of large populations within ethnic groups obviate this effect [Morton and Collins, 1998]. Furthermore, a family-based test also failed to con®rm the original observations and studies on Japanese AD cases, known to be a genetic isolate, also failed to con®rm this association [Shibata et al, 1999;Higuchi et al, 2000].…”

Section: Discussionmentioning

confidence: 99%

Common polymorphisms in LRP and A2M do not affect genetic risk for Alzheimer disease in Northern Ireland

McIlroy¹,

Dynan²,

Vahidassr³

et al. 2001

Am. J. Med. Genet.

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“…These possibilities are not mutually exclusive and could help to explain the nearly compete suppression of the ApoE4 effect, if they occur in combination. Whereas this is the first report that ␣2M negatively interferes with neuronal cell death caused by AD gene products, this ␣2M antagonism against ApoE4 concurs with recent reports Liao et al, 1998;Alvarez et al, 1999;Dodel et al, 2000;Romas et al, 2000) that polymorphisms of ␣2M are genetically associated with AD, although this association is controversial (Kovacs et al, 1999;Gibson et al, 2000;Higuchi et al, 2000;Sodeyama et al, 2000).…”

Section: Discussionsupporting

confidence: 87%

Neuronal Apoptosis by Apolipoprotein E4 through Low-Density Lipoprotein Receptor-Related Protein and Heterotrimeric GTPases

et al. 2000

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The ⑀4 genotype of apolipoprotein E (apoE4) is the most established predisposing factor in Alzheimer's disease (AD); however, it remains unclear how apoE4 contributes to the pathophysiology. Here, we report that the apoE4 protein (ApoE4) evokes apoptosis in neuronal cells through the low-density lipoprotein receptor-related protein (LRP) and heterotrimeric GTPases. We examined neuron/neuroblastoma hybrid F11 cells and found that these cells were killed by 30 g/ml ApoE4, but not by 30 g/ml ApoE3. ApoE4-induced death occurred with typical features for apoptosis in time-and dose-dependent manners, and was observed in SH-SY5Y neuroblastomas, but not in glioblastomas or non-neuronal Chinese hamster ovary cells. Activated, but not native, ␣2-macroglobulin suppressed this ApoE4 toxicity. Suppression by the antisense oligonucleotide to LRP and inhibition by low nanomolar concentrations of LRP-associated protein RAP provided evidence for the involvement of LRP. The involvement of heterotrimeric GTPases was demonstrated by the findings that (1) ApoE4-induced death was suppressed by pertussis toxin (PTX), but not by heat-inactivated PTX; and (2) transfection with PTX-resistant mutant cDNAs of G␣ i restored the toxicity of ApoE4 restricted by PTX. We thus conclude that one of the neurotoxic mechanisms triggered by ApoE4 is to activate a cell type-specific apoptogenic program involving LRP and the G i class of GTPases and that the apoE4 gene may play a direct role in the pathogenesis of AD and other forms of dementia.

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“…A process unrelated to apoE actions in neuronal repair and remodeling may also hold the clue for understanding its involvement in PD. 19,20 The present study demonstrates that the existing literature as a whole [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] (see figures 2, 3, and table E-2 on the Neurology Web site for references) supports a positive association between an APOE polymorphism and sporadic PD disease. 18 In the past, almost every reported association of gene polymorphism and PD has been contradicted by other studies.…”

Section: Discussionsupporting

confidence: 65%

APOE-ε2 allele associated with higher prevalence of sporadic Parkinson disease

Huang

Chen²,

Poole³

2004

Neurology

146

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α2-Macroglobulin gene polymorphisms show racial diversity and are not associated with Alzheimerʼs disease

Cited by 20 publications

References 1 publication

Common polymorphisms in LRP and A2M do not affect genetic risk for Alzheimer disease in Northern Ireland

Common polymorphisms in LRP and A2M do not affect genetic risk for Alzheimer disease in Northern Ireland

Neuronal Apoptosis by Apolipoprotein E4 through Low-Density Lipoprotein Receptor-Related Protein and Heterotrimeric GTPases

APOE-ε2 allele associated with higher prevalence of sporadic Parkinson disease

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