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Published 14 March 2005. doi:10.1083/jcb.200410047
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 6, 863-868
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Report

 ß-site specific intrabodies to decrease and prevent generation of Alzheimer's Aß peptide

Paolo Paganetti2, Verena Calanca1, Carmela Galli1, Muriel Stefani2, and Maurizio Molinari1

1 Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland
2 Novartis Institutes for Biomedical Research Basel, Neuroscience Research, Novartis Pharma AG, CH-4002 Basel, Switzerland

Correspondence to Maurizio Molinari: Maurizio.molinari{at}irb.unisi.ch


Abstract
Endoproteolysis of the ß-amyloid precursor protein (APP) by ß- and {gamma}-secretases generates the toxic amyloid ß-peptide (Aß), which accumulates in the brain of Alzheimer's disease (AD) patients. Here, we established a novel approach to regulate production of Aß based on intracellular expression of single chain antibodies (intrabodies) raised to an epitope adjacent to the ß-secretase cleavage site of human APP. The intrabodies rapidly associated, within the endoplasmic reticulum (ER), with newly synthesized APP. One intrabody remained associated during APP transport along the secretory line, shielded the ß-secretase cleavage site and facilitated the alternative, innocuous cleavage operated by {alpha}-secretase. Another killer intrabody with an ER retention sequence triggered APP disposal from the ER. The first intrabody drastically inhibited and the second almost abolished generation of Aß. Intrabodies association with specific substrates rather than with enzymes, may modulate intracellular processes linked to disease with highest specificity and may become instrumental to investigate molecular mechanisms of cellular events.

Abbreviations used in this paper: Aß, amyloid ß-peptide; AD, Alzheimer's disease; APP, ß-amyloid precursor protein; BACE, ß-site APP cleaving enzyme; HEK, human embryonic kidney 293; PS, PBS and permeabilized with 0.05% saponin.


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