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

ABSTRACT 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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    ABSTRACT: The toxicity of amyloid β and tau, the two hallmark proteins in Alzheimer's disease (AD), has been extensively studied individually. Recently new data suggest their possible interactions and synergistic effects in the disease. In this study, we investigate the ability of antibodies against the β secretase cleavage site on APP, named BBS1, to affect tau pathology, besides their well established effect on intracellular Aβ and amyloid load. For this purpose we treated the triple transgenic mice model of AD (3x Tg-AD) with mAb BBS1 intracerebroventricularly, using mini osmotic pumps for one month. The experimental data demonstrated reduction in total and phosphorylated tau levels, explained by significant reduction in GSK3β which phosphorylates tau on sites recognized by antibodies against PHF1 and AT-8. The treatment increased the cognitive capabilities and reduced the brain inflammation levels which accompany AD pathology. The data showing that tau pathology was significantly reduced by BBS1 antibodies suggest a close interaction between tau and Aβ in the development of AD, and may serve as an efficient novel immunotherapy against both hallmarks of this disease.
    PLoS ONE 10/2012; 7(10):e46650. DOI:10.1371/journal.pone.0046650 · 3.23 Impact Factor
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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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    ABSTRACT: Alzheimer's disease is characterized pathologically by extracellular senile plaques, intracellular neurofibrillary tangles, and granulovacuolar degeneration. It has been debated whether these hallmark lesions are markers or mediators of disease progression, and numerous paradigms have been proposed to explain the appearance of each lesion individually. However, the unfaltering predictability of these lesions suggests a single pathological nidus central to disease onset and progression. One of the earliest pathologies observed in Alzheimer's disease is endocytic dysfunction. Here we review the recent literature of endocytic dysfunction with particular focus on disrupted lysosomal fusion and propose it as a unifying hypothesis for the three most-studied lesions of Alzheimer's disease.
    International Journal of Alzheimer's Disease 08/2012; 2012(11):752894. DOI:10.1155/2012/752894
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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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    ABSTRACT: Alzheimer's disease (AD) is the major form of age-related dementia and is characterized by progressive cognitive impairment, the accumulation of extracellular amyloid β-peptide (Aβ), and intracellular hyperphosphorylated tau aggregates in affected brain regions. Tau hyperphosphorylation and accumulation in neurofibrillary tangles is strongly correlated with cognitive deficits, and is apparently a critical event in the dementia process because mutations in tau can cause a tangle-only form of dementia called frontotemporal lobe dementia. Among kinases that phosphorylate tau, glycogen synthase kinase 3β (GSK3β) is strongly implicated in AD pathogenesis. In the present study, we established an ELISA to screen for agents that inhibit GSK3β activity and found that the flavonoid morin effectively inhibited GSK3β activity and blocked GSK3β-induced tau phosphorylation in vitro. In addition, morin attenuated Aβ-induced tau phosphorylation and protected human neuroblastoma cells against Aβ cytotoxicity. Furthermore, treatment of 3xTg-AD mice with morin resulted in reductions in tau hyperphosphorylation and paired helical filament-like immunoreactivity in hippocampal neurons. Morin is a novel inhibitor of GSK3β that can reduce tau pathology in vivo and may have potential as a therapeutic agent in tauopathies.
    Neurobiology of Disease 07/2011; 44(2):223-30. DOI:10.1016/j.nbd.2011.07.005 · 5.08 Impact Factor
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