The Interaction Between Trancations Of Pronts And Sortilin And The Effect Of Recombinant Protein P75^NTR/Fc To Aβ25-35Induced PC12Apoptosis

Alzheimer’s disease (AD) is a progressive neurological disorder characterized by the loss of memory and cognitive functions. The neuropathology is characterized by key features that include selective loss of neurons and synapses, formation of neurofibrillary tangles composed of hyperphosphorylated tau protein and the amyloid β-peptide (Aβ) deposition into dense senile plaques. The exact mechanism that causes AD is not completely understood. However, substantial papers implicate the precursor forms of NGF and Aβ in the process.NGF is synthesized as precursor forms that are cleaved by proteinase to release C-terminal mature forms that bind to Trk and p75NTR receptors to initiate survival and differentiative function. Recent studies suggest that in the neurons of injury or neurodegenerative diseases, the precursor form of neurotrophins escape the cleavage and bind to p75NTR and sortilin receptors to initiate cell death. During the interation of proNTs-p75NTR-sortilin, the pro-domain and the’mature’part of proNTs engage sortilin and p75NTR respectively. Sortilin is essential for proNT-induced cell death and acts as a molecular switch governing the p75NTR and sortilin mediated pro-apoptosis signal induced by proNTs. During the first part of our study, we try to confirm that the pro-domain of proNGF and proBDNF could interact with sortilin, so they can compete with sortilin to interact with proNTs to reduce the cell death.The senile plaques are deposited of Aβ derived from the abnomal cleavage of the amyloid precursor protein (APP). Many papers report that AB induces neuronal death by binding the transmembrane75KDa neurotrophin receptor (p75NTR). In the second part of our study, we show A(3(25-35) peptide induces neurotoxicity in undifferentiated PC12cell. We also get the fusion protein of p75NTR extracellular domain and human IgG Fc fragment (p75NTR/Fc) by the prokaryotic expression system. We show that Ap-mediated p75NTR signaling is blocked by the fusion protein that compete with p75NTR binding to Aβ, significantly increasing neuronal viability. We also show that the fusion protein can compete with p75NTR binding to NGF, inhibiting the neurite growth induced by NGF.