BACE inhibitor reduces APP-beta-C-terminal fragment accumulation in axonal swellings of okadaic acid-induced neurodegeneration.

Neurobiol Dis 2006 May 9;22(2):435-44. Epub 2006 Feb 9.

Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, South Korea.

Emerging evidence suggests that not only beta-amyloid but also other amyloid precursor protein (APP) fragments, such as the beta-C-terminal fragment (betaCTF), might be involved in Alzheimer's disease (AD). Treatment of neurons with okadaic acid (OA), a protein phosphatase-2A inhibitor, has been used to induce tau phosphorylation and neuronal death to create a research model of AD. In this study, we analyzed axonopathy and APP regulation in cultured rat neurons treated with OA. After OA treatment, the neurons presented with axonal swellings filled with vesicles, microtubule fragments, and transport molecules such as kinesin and synapsin-I. Western blotting showed that intracellular APP levels were increased and immunocytochemistry using antibodies against the APP C-terminus showed that APP accumulated in the axonal swellings. This APP C-terminus immunoreactivity disappeared when neurons were cotreated with a beta-secretase inhibitor, but not with alpha- or gamma-secretase inhibitors, indicating that the accumulation was primarily composed of APP-betaCTF. These findings provide the first evidence that APP-betaCTF can accumulate in the axons of OA-treated neurons, and may suggest that APP-betaCTF is involved in the pathogenesis of AD.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2005.12.013DOI Listing
May 2006
8 Reads

Publication Analysis

Top Keywords

axonal swellings
12
app c-terminus
8
treatment neurons
8
app
6
neurons
5
regulation cultured
4
study analyzed
4
app accumulated
4
model study
4
inhibitors indicating
4
gamma-secretase inhibitors
4
analyzed axonopathy
4
levels increased
4
alpha- gamma-secretase
4
create model
4
axonopathy app
4
app regulation
4
increased immunocytochemistry
4
induce tau
4
composed app-betactf
4

Similar Publications