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

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.

RNA-Dependent Amplification of Mammalian mRNA Encoding Extracellular Matrix Components: Identification of Chimeric RNA Intermediates for α1, β1, and γ1 Chains of Laminin

“…Likewise is their origin: these molecules are clearly produced by the extension of the 3'terminus of antisense RNA self-primed in a sequence-specific manner. These results can be interpreted within the framework of the mRNA amplification model developed and postulated in more detailed previous studies (1,2,(11)(12)(13)(14)(15)(16)(17)(18) of terminally differentiating cells where the putative mRNA end product of the amplification process accumulates to extraordinary high levels, constituting nearly a tenth of total ribosomal RNA (2). The findings of the present study are fully consistent with the postulated mechanism of mRNA amplification.…”

“…The findings of the present study are fully consistent with the postulated mechanism of mRNA amplification. Moreover, the possible occurrence of chimeric molecules in cells overproducing a specific protein, such as our study model, was predicted by the postulated amplification mechanism (1,2,18). The results of the present study constitute a confirmation of this prediction and validate the proposed mechanism.…”

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

“…One possible explanation for such an incongruity might be related to the difference in the genetic background between mice and humans. Such a genetic difference between the two species was fruitfully discussed before . However, the persistent negative results of BACE1 inhibitors in clinical trials should not be overlooked since these results contain important lessons to the future.…”

“…Such a genetic difference between the two species was fruitfully discussed before. 36,37 However, the persistent negative results of BACE1 inhibitors in clinical trials should not be overlooked since these results contain important lessons to the future. While some understood these findings as a judgment of amyloid cascade hypothesis (ACH) validity, however, such a conclusion appears to be premature; since the ACH remains the most recognized theory when compared with other alternative interpretations of AD pathology.…”

Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1

“…18 Thus, BACE1 inhibition is a major therapeutic approach for AD and several BACE1-targeting inhibitors have been advanced into phase 3 clinical trials. 19 However, several side effects were observed in some phase 3 trials, such as psychiatric symptoms and increased falls, [20][21][22] which may be mechanism-based because BACE1 does not only cleave APP, but has multiple additional substrates with functions in the nervous system. 23 Moreover, BACE1 KO mice show several phenotypes, revealing a fundamental function for BACE1 in the nervous system.…”