Inhibition of amyloid precursor protein processing by -secretase through site-directed antibodies

Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2005; 102(21):7718-23. DOI: 10.1073/pnas.0502427102
Source: PubMed


Amyloid-beta peptide (AbetaP) that accumulates in the Alzheimer's diseased brain is derived from proteolytic processing of the amyloid precursor protein (APP) by means of beta- and gamma-secretases. The beta-secretase APP cleaving enzyme (BACE), which generates the N terminus of AbetaP, has become a target of intense research aimed at blocking the enzyme activity, thus reducing AbetaP and, subsequently, plaque formation. The search for specific inhibitors of beta-secretase activity as a possible treatment for Alzheimer's disease intensified with the discovery that BACE may be involved in processing other non-APP substrates. The presence of the APP-BACE complex in early endosomes highlights the cell surface as a potential therapeutic target, suggesting that interference in APP-BACE interaction at the cell surface may affect amyloid-beta production. We present here a unique approach to inhibit AbetaP production by means of antibodies against the beta-secretase cleavage site of APP. These antibodies were found to bind human APP overexpressed by CHO cells, and the formed immunocomplex was visualized in the early endosomes. Indeed, blocking of the beta-secretase site by these antibodies interfered with BACE activity and inhibited both intracellular and extracellular AbetaP formation in these cells.

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Available from: Beka Solomon, Dec 12, 2013
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    • "These antibodies bind both wild-type and Swedish-mutated APP expressed in transgenic mouse brain tissues and do not bind any form of Aβ peptides [28]. Administration of these antibodies to the cells [15] and to transgenic mice models of AD [16], [17] resulted in a considerable decrease in intracellular Aβ levels including toxic oligomers. The relevance of intraneuronal accumulation of mainly Aβ42 as an early event in AD pathogenesis suggests that this approach may be applicable as a novel therapeutic strategy in AD treatment. "
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    • "The presence of Aβ in early endosomes also is consistent with the colocalization of APP and BACE1 within the same early endocytic compartments [39] [40] [41] [42] and the degradation of BACE within the endosomal-lysosomal system [43]. One study suggests that internalized Aβ can aggregate within the cell and disrupt the vesicular membrane, thus contributing to its pathologic effect [44]. "
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    • "Because AD is characterized by the abnormal accumulation of Aβ plaques, most studies have targeted β-secretase (BACE) and γ-secretase to modulate sequential proteolytic cleavage of APP so as to reduce Aβ production (Arbel et al., 2005; Evin and Kenche, 2007; Jo et al., 2010; Nunan and Small, 2000; Vassar et al., 1999). Unfortunately, in a recent major clinical trial, a γ-secretase inhibitor exacerbated the cognitive decline in AD patients (Extance), likely because of off-target actions of γ-secretase in the Notch signaling pathway (Wang et al., 2004). "
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