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Med. Sci. 2018, 6(2), 45; https://doi.org/10.3390/medsci6020045

Results of Beta Secretase-Inhibitor Clinical Trials Support Amyloid Precursor Protein-Independent Generation of Beta Amyloid in Sporadic Alzheimer’s Disease

1
Deptartment of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA
2
Howard Hughes Medical Institute at Children’s Hospital, Boston, MA 02115, USA
3
Deptartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
Received: 26 April 2018 / Revised: 20 May 2018 / Accepted: 29 May 2018 / Published: 2 June 2018
(This article belongs to the Collection Advances in the Pathogenesis of Neurodegenerative Diseases)
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Abstract

The present review analyzes the results of recent clinical trials of β secretase inhibition in sporadic Alzheimer’s disease (SAD), considers the striking dichotomy between successes in tests of β-site Amyloid Precursor Protein-Cleaving Enzyme (BACE) inhibitors in healthy subjects and familial Alzheimer’s disease (FAD) models versus persistent failures of clinical trials and interprets it as a confirmation of key predictions for a mechanism of amyloid precursor protein (APP)-independent, β secretase inhibition-resistant production of β amyloid in SAD, previously proposed by us. In light of this concept, FAD and SAD should be regarded as distinctly different diseases as far as β-amyloid generation mechanisms are concerned, and whereas β secretase inhibition would be neither applicable nor effective in the treatment of SAD, the β-site APP-Cleaving Enzyme (BACE) inhibitor(s) deemed failed in SAD trials could be perfectly suitable for the treatment of FAD. Moreover, targeting the aspects of Alzheimer’s disease (AD) other than cleavages of the APP by β and α secretases should have analogous impacts in both FAD and SAD. View Full-Text
Keywords: Alzheimer’s disease; amyloid precursor protein; familial Alzheimer’s disease; sporadic Alzheimer’s disease; β-site amyloid precursor protein-cleaving enzyme 1 inhibitors; amyloid precursor protein-independent generation of β amyloid Alzheimer’s disease; amyloid precursor protein; familial Alzheimer’s disease; sporadic Alzheimer’s disease; β-site amyloid precursor protein-cleaving enzyme 1 inhibitors; amyloid precursor protein-independent generation of β amyloid
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Volloch, V.; Rits, S. Results of Beta Secretase-Inhibitor Clinical Trials Support Amyloid Precursor Protein-Independent Generation of Beta Amyloid in Sporadic Alzheimer’s Disease. Med. Sci. 2018, 6, 45.

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