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APP carboxyl-terminal fragment without or with abeta domain equally induces cytotoxicity in differentiated PC12 cells and cortical neurons.

Abstract：

:Mutations in the beta-amyloid precursor protein (APP) gene cause familial Alzheimer's disease (AD). Although amyloid beta peptide (Abeta) is the principal constituent of senile plaques in AD, other cleavage products of APP are also implicated in playing a role in the pathogenesis of AD. C-terminal fragments of APP (APP-CTs), that contain complete Abeta sequence, are found in neuritic plaques, neurofibrillary tangles and the cytosol of lymphoblastoid cells obtained from AD patients. Our previous report demonstrated that APP-CT105 causes death of differentiated PC12 cells and cultured rat cortical neurons (Kim and Suh [1996] J. Neurochem. 67:1172-1182) and induces strong inward currents in Xenopus oocyte (Fraser et al., [1996] J. Neurochem. 66:2034-2040). In the present study, to investigate which domain of APP-CT105 is responsible for the neurotoxicity, we have made deletion mutants of APP-CT105 without Abeta and transmembrane domain (TM) or without NPTY domain, a putative endocytosis signaling sequence, using the PCR-amplified strategy and the recombinant GST-fusion protein strategy. The effect on cell survival of the deletion mutants of APP-CT105 (8 microM) was then determined by the LDH and MTT assay. We found that C-terminal fragment without NPTY significantly causes cell death in NGF-differentiated PC12 cells and cultured rat cortical neurons. This finding suggests that NPTY may not play an important role in APP-CT105 mediated neurotoxicity. We found, however, that C-terminal fragment without Abeta and TM significantly induces neuronal cell death. Our results suggest that in addition to Abeta, C-terminal fragment of APP without Abeta and TM domain itself may also participate in the neuronal degeneration in AD.

journal_name

J Neurosci Res

journal_title

Journal of neuroscience research

authors

Lee JP,Chang KA,Kim HS,Kim SS,Jeong SJ,Suh YH

doi

10.1002/(SICI)1097-4547(20000515)60:4<565::AID-JNR

keywords:

subject

Has Abstract

pub_date

2000-05-15 00:00:00

pages

565-70

issue

eissn

0360-4012

issn

1097-4547

pii

10.1002/(SICI)1097-4547(20000515)60:4<565::AID-JNR

journal_volume

pub_type

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APP carboxyl-terminal fragment without or with abeta domain equally induces cytotoxicity in differentiated PC12 cells and cortical neurons.