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.

Keywords: Alzheimer’s disease; amyloid precursor protein; amyloid precursor protein-independent generation of β amyloid; familial Alzheimer’s disease; sporadic Alzheimer’s disease; β-site amyloid precursor protein-cleaving enzyme 1 inhibitors.

Figure 1

RdRp-mediated amplification of mRNA can result in a 5′-truncated molecule encoding C-terminal fragment of a conventional polypeptide. Boxed line—sense strand RNA. Single line—antisense strand RNA. “AUG”—functional translation initiation codon. “TCE”—3′-terminal complementary element; “ICE”—internal complementary element, both on the antisense strand. Yellow circle—helicase/modifying activity complex. Blue lines (both single and boxed)—RNA strand modified and separated from its complement by a helicase complex. Red arrowhead—position of cleavage of the chimeric intermediate. Top panel—conventional genome-transcribed mRNA molecule. Middle panel—“AUG” is the translation initiation codon of a conventional mRNA and “ICE” of the antisense strand is located within its segment corresponding to the 5′UTR. Chimeric RNA end product contains an intact coding region of a conventional mRNA progenitor and can be translated into the original, conventional mRNA-encoded, polypeptide. Bottom panel—“ICE” is located within a segment of antisense RNA corresponding to the coding region of mRNA. The amplified RNA contains a 5′-truncated coding region of the conventional mRNA progenitor. The translational outcome is decided by the position of the first functional AUG; if in-frame, it initiates translation of a C-terminal fragment of the conventional polypeptide. Steps 3′–7′ correspond to steps 3–7 of the middle panel.

Figure 2

Projected topology of RdRp-mediated generation of 5′-truncated human βAPP mRNA encoding C99 fragment of βAPP. Lowercase letters—nucleotide sequence of the antisense strand. Uppercase letters—nucleotide sequence of the sense RNA strand. Yellow boxes—TCE (top) and ICE (bottom) elements of the antisense strand. Asterisks, (−146) and (−149)—positions on the antisense strand corresponding to transcriptional start sites (TSSs) of human βAPP mRNA (numbering from the AUG translation initiation codon of conventional mRNA). “2011–2013”—positions on the antisense strand of the “uac” (highlighted in turquoise) corresponding to the “AUG” (highlighted in green) encoding Met671 (isoform 770 numbering) in the conventional βAPP mRNA. (a)—TCE/ICE-guided folding of the antisense strand of βAPP mRNA. Note that complementary elements are separated by nearly 2000 nucleotides. (b)—Extension of self-primed antisense strand into sense-orientation RNA and cleavage (after strands-separation) of chimeric intermediate. Note the “AUG” codon (highlighted in green and encoding Met671 in the conventional APP mRNA) 58 nucleotides downstream from the TCE. (c)—Chimeric end product contains, at its 5′ terminus, an antisense sequence (TCE, shown in lowercase letters) extending into severely 5′-truncated βAPP mRNA (shown in uppercase letters). Its translation is initiated from the AUG (highlighted in green) encoding Met 671 (isoform 770 numbering) in the conventional mRNA and it encodes C99 fragment of βAPP.