1. Alzheimer's-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition.
- Author
-
Jiang Y, Mullaney KA, Peterhoff CM, Che S, Schmidt SD, Boyer-Boiteau A, Ginsberg SD, Cataldo AM, Mathews PM, and Nixon RA
- Subjects
- Adolescent, Adult, Alzheimer Disease complications, Alzheimer Disease drug therapy, Alzheimer Disease genetics, Amyloid Precursor Protein Secretases genetics, Amyloid beta-Peptides metabolism, Aspartic Acid Endopeptidases genetics, Cells, Cultured, Child, Child, Preschool, Down Syndrome complications, Down Syndrome genetics, Fibroblasts metabolism, Humans, Infant, Protein Transport, Superoxide Dismutase genetics, Superoxide Dismutase metabolism, Superoxide Dismutase-1, Young Adult, Alzheimer Disease metabolism, Amyloid Precursor Protein Secretases metabolism, Amyloid beta-Protein Precursor metabolism, Aspartic Acid Endopeptidases metabolism, Down Syndrome metabolism, Endosomes metabolism, RNA Interference
- Abstract
An additional copy of the beta-amyloid precursor protein (APP) gene causes early-onset Alzheimer's disease (AD) in trisomy 21 (DS). Endosome dysfunction develops very early in DS and AD and has been implicated in the mechanism of neurodegeneration. Here, we show that morphological and functional endocytic abnormalities in fibroblasts from individuals with DS are reversed by lowering the expression of APP or beta-APP-cleaving enzyme 1 (BACE-1) using short hairpin RNA constructs. By contrast, endosomal pathology can be induced in normal disomic (2N) fibroblasts by overexpressing APP or the C-terminal APP fragment generated by BACE-1 (betaCTF), all of which elevate the levels of betaCTFs. Expression of a mutant form of APP that cannot undergo beta-cleavage had no effect on endosomes. Pharmacological inhibition of APP gamma-secretase, which markedly reduced Abeta production but raised betaCTF levels, also induced AD-like endosome dysfunction in 2N fibroblasts and worsened this pathology in DS fibroblasts. These findings strongly implicate APP and the betaCTF of APP, and exclude Abeta and the alphaCTF, as the cause of endocytic pathway dysfunction in DS and AD, underscoring the potential multifaceted value of BACE-1 inhibition in AD therapeutics.
- Published
- 2010
- Full Text
- View/download PDF