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BETA AMYLOID BINDS TRIMERS AS WELL AS MONOMERS OF THE 75 kDNEUROTROPHIN RECEPTOR AND ACTIVATES RECEPTOR SIGNALING

Mina Yaar 1,4 , Sen Zhai 1 , Richard E. Fine 3,4,5 , Patricia B. Eisenhauer 4,5 Bennett L. Arble 1 Kenneth B. Stewart 1 and Barbara A. Gilchrest 1,2,4

 

Boston University School of Medicine,

Departments of 1 Dermatology, 2 Biochemistry, 3 Neurology and 4 Pathology,

715 Albany Street,

Boston, MA 02118;

 

and 5 Department of Veterans Affairs,

VA Medical Center,

200 Springs Road,

Bedford, MA 01730

 

Keywords: Alzheimer's disease, beta amyloid, receptors, signaling, apoptosis

Summary

p75 NTR , a nerve growth factor co-receptor that has been implicated in apoptosis of neurons, is structurally related to Fas and the receptors for tumor necrosis factor- that display ligand independent assembly into trimers. Using E17 fetal rat cortical neurons and p75 NTR expressing NIH-3T3 cells, we now show that p75 NTR exists as a trimer as well as a monomer, independent of ligand binding. Furthermore, we have reported and others have confirmed that amyloid binds p75 NTR , and that this binding leads to apoptotic cell death. We now report that amyloid binds to trimers of p75 NTR as well as to p75 NTR monomers but not to the p140 trkA , the nerve growth factor co-receptor that mediates neuronal survival. Furthermore, amyloid activates p75 NTR , strongly inducing the transcription of c-jun mRNA and stimulating the stress-activated c-Jun NH2-terminal kinase (JNK) as measured by phosphorylation of its substrate [GST-cJun (1-79)]. Our data suggest that p75 NTR is present as a preformed complex that binds amyloid to induce receptor activation, and support the hypothesis that p75 NTR activation by amyloid is causally related to Alzheimer's disease.

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journal biological chemistry