α2 Macroglobulin and the risk of Alzheimer’s disease

Dodel, Richard; Du, Yansheng; Bales, Kelly R.; Gao, Feng; Eastwood, Brian J.; Glazier, Bradley S.; Zimmer, R.; Cordell, Barbara; Hake, Ann Marie; Evans, Rebecca M.; Gallagher‐Thompson, Dolores; Thompson, Larry W.; Tinklenberg, Jared R.; Pfefferbaum, Adolf; Sullivan, E. V.; Yesavage, Jerome A.; Altstiel, Larry D.; Gasser, Thomas; Farlow, Martin R.; Murphy, Greer M.; Paul, Steven M.

doi:10.1212/wnl.54.2.438

Cited by 69 publications

(31 citation statements)

References 30 publications

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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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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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“…Genetic association of A2M with AD was also noted in the Finnish elderly population [16]. Similar results were reported in the USA [5,7,13]. These data seem to support the view about susceptibility for AD, linked to A2M polymorphism.…”

Section: Introductionsupporting

confidence: 83%

Original article On the lack of a clear-cut association between alpha-2-macroglobulin deletion and the risk of Alzheimer disease in Poland

Michałowska-Wender

Wawrzynek²,

G³

et al. 2014

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A b s t r a c t Alzheimer disease (AD) is a complex, multi-factorial disease with the potential involvement of several genes. Alpha-2-macroglobulin (A2M) has been implicated in AD on the basis of its ability to mediate the clearance and degradation of β-amyloid peptide. Nevertheless, it is not clear whether there are racial differences in frequency of polymorphisms of A2M in AD. We examined a group of 50 unrelated patients from Poland (38 women and 12 men), who were diagnosed clinically as probably developing AD (according to the N1NCD3 -ADR PA criteria). The patients were examined by a neurologist and a psychologist and had a CT or MRI scan of the brain. Fifty individuals of matched age, withoutany signs of dementia, were studied as a control group. DNA was extracted by a routine method from a blood sample. Amplification and genotyping at A2M was performed as described by Blacker et al. (1997). The genotypic distribution in A2M exon 18 in patients with AD and genotype TT in A2M exon 24 was similar to that in the controls. Significant differences were noted only in early onset AD in males and for old onset disease in females. The deletions were found more frequently in AD; however, they were found in only a small proportion of studied patients. These findings indicate that A2M is not the only biological candidate gene for AD determination.

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“…Previous studies have indicated that there may be alterations in the levels of proteins that attenuate Ab fibrillization, namely a2M 155 and SAP 156 in AD patients, although there are also conflicting data on this issue. It should be noted that polymorphism in the a2M gene may be associated with AD risk in some populations and may be influenced by family history (for example references [157][158][159][160][161][162] ), although these findings are controversial. Decreased SAP levels have also been correlated with impaired cognitive performance in aged individuals 163 and in clinically diagnosed AD.…”

Section: Ab-binding Proteins In Blood Plasmamentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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α2 Macroglobulin and the risk of Alzheimer’s disease

Abstract: Our data support an association between the A2M gene and AD. This association is less pronounced, however, in our cohort than in the previously reported sample of sibpairs.

Cited by 69 publications

References 30 publications

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

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

Original article On the lack of a clear-cut association between alpha-2-macroglobulin deletion and the risk of Alzheimer disease in Poland

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

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