Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer's disease.

Yaar, Mina; Zhai, Shengli; Pilch, Paul F.; Doyle, Sineaid; Eisenhauer, Patricia B.; Fine, Richard E.; Gilchrest, Barbara A.

doi:10.1172/jci119772

Cited by 323 publications

(272 citation statements)

References 58 publications

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“…Whereas F11 cells per se were not killed by A␤1-43, as reported previously (9,19), cell death was induced by A␤1-43 when F11 cells were transfected with the p75 neurotrophin receptor p75 NTR (Table II). This is in agreement with the notion that p75 NTR mediates A␤ neurotoxicity, as has been shown by multiple studies (33)(34)(35). When p75 NTR -transfected F11 cells were co-transfected with hGtx, cell death by 25 M A␤1-43 was drastically suppressed (Table II).…”

Section: Resultssupporting

confidence: 91%

The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain

Hashimoto

Tsuji

Kanekura

et al. 2004

Journal of Biological Chemistry

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Section: Resultssupporting

confidence: 91%

The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain

Hashimoto

Tsuji

Kanekura

et al. 2004

Journal of Biological Chemistry

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“…p75 NTR expression is up-regulated after axotomy or neuronal injury, and p75 NTR antisense oligonucleotides have been shown to reduce the damage (67)(68)(69). The ␤-amyloid peptide that is accumulating as extracellular deposits during the progression of Alzheimer's disease has been shown to bind and activate p75 NTR (70,71). The cellular model presented here will be a valuable tool for mass screening of anti-apoptotic compounds that may have a benefit to treat these and perhaps other neurological disorders where p75 NTR has been implicated.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a p75NTR Apoptotic Signaling Pathway Using a Novel Cellular Model

Wang¹,

Bauer²,

Li³

et al. 2001

Journal of Biological Chemistry

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The p75 neurotrophin receptor (p75 NTR ) belongs to the tumor necrosis factor receptor/nerve growth factor receptor superfamily. In some cells derived from neuronal tissues it causes cell death through a poorly characterized pathway. We developed a neuronal system using conditionally immortalized striatal neurons, in which the expression of p75 NTR is inducibly controlled by the ecdysone receptor. In these cells p75 NTR induces apoptosis through its death domain in a nerve growth factor-independent manner. Caspases 9, 6, and 3 are activated by receptor expression indicating the activation of the common effector pathway of apoptosis. Cell death is blocked by a dominant negative form of caspase 9 and Bcl-X L consistent with a pathway that involves mitochondria. Significantly, the viral flice inhibitory protein E8 protects from p75 NTR -induced cell death indicating that death effector domains are involved. A p75 NTR construct with a deleted death domain dominantly interferes with p75 NTR signaling, implying that receptor multimerization is required. However, in contrast to the other receptors of the family, p75 NTR -mediated apoptosis does not involve the adaptor proteins Fas-associated death domain protein or tumor necrosis factor-associated death domain protein, and the apical caspase 8 is not activated. We conclude that p75 NTR signals apoptosis by similar mechanisms as other death receptors but uses different adaptors and apical caspases.

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“…44 Recent experimental data also suggest that b-amyloid protein binds to p75 NTR , and this binding can lead to apoptosis. 45 However, the most compelling evidence for the direct involvement of p75 NTR in neuronal degeneration under pathologic conditions may be the observations on cell death following both pilocarpine induced seizure activity and unilateral kainic acid administration. The effects of both insults correlate strongly with the expression of p75 NTR in hippocampus, cortex and basal forebrain regions.…”

Section: Discussionmentioning

confidence: 99%

Zinc inhibits p75NTR-mediated apoptosis in chick neural retina

et al. 2001

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It has previously been documented that Zn 2+ inhibits TrkAmediated effects of NGF. To evaluate the ability of Zn 2+ to attenuate the biological activities of NGF mediated by p75 NTR , we characterized the effects of this transition metal cation on both binding and the pro-apoptotic properties of the NGFp75 NTR interaction. Binding of NGF to p75 NTR displayed higher affinity in embryonic chick retinal cells than in PC12 cells. NGF induced apoptosis in dissociated cultures of chick neural retina. The addition of 100 mM Zn 2+ inhibited binding and chemical cross-linking of 125 I-NGF to p75 NTR , and also attenuated apoptosis mediated by this ligand-receptor interaction. These studies lead to the conclusion that Zn 2+ antagonizes NGF/p75 NTR -mediated signaling, suggesting that the effect of this transition metal cation can be either pro-or anti-apoptotic depending on the cellular context. Cell Death and Differentiation (2001) 8, 451 ± 456.

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Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer's disease.

Cited by 323 publications

References 58 publications

The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain

The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain

Characterization of a p75NTR Apoptotic Signaling Pathway Using a Novel Cellular Model

Zinc inhibits p75NTR-mediated apoptosis in chick neural retina

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