| First Author | Davis W Jr | Year | 2010 |
| Journal | Curr Alzheimer Res | Volume | 7 |
| Issue | 7 | Pages | 566-77 |
| PubMed ID | 20704561 | Mgi Jnum | J:277904 |
| Mgi Id | MGI:6356260 | Doi | 10.2174/156720510793499002 |
| Citation | Davis W Jr (2010) The ATP-binding cassette transporter-2 (ABCA2) increases endogenous amyloid precursor protein expression and Abeta fragment generation. Curr Alzheimer Res 7(7):566-77 |
| abstractText | The ATP binding cassette transporter-2 (ABCA2) has been genetically linked to Alzheimer's disease but the molecular mechanisms are unknown. In this study, the effects of expression of human ABCA2 on endogenous amyloid precursor protein (APP) expression, trafficking and processing were examined in mouse N2a neuronal cells. ABCA2 expression increased the steady-state APP mRNA levels through transcription. ABCA2 also induced increased synthesis of APP holoprotein and altered APP processing and metabolite generation. ABCA2 expression promoted b-secretase (BACE1) cleavage of APP not at the common Asp1 amino acid site (beta-site) of Abeta in APP but at the Glu11 site (beta'-site) to increase C89 carboxyl-terminal fragment levels (beta'-CTF/C89). The levels of N-terminally truncated Abeta11-40 peptides were also increased by ABCA2 expression. The delivery of newly synthesized APP to the cell surface through the secretary pathway was not perturbed by ABCA2 expression; however, ABCA2 expression increased the amount of APP in early-endosomal compartments, which also contained the highest levels of beta'-CTF/C89 and is likely the site of increased BACE1 processing of APP. This report identifies ABCA2 as a key regulator of endogenous APP expression and processing and suggests a possible biochemical mechanism linking ABCA2 expression, APP processing and Alzheimer's disease. |
