A mechanism for beta-amyloid overproduction in Alzheimer's disease: precursor-independent generation of beta-amyloid via antisense RNA-primed mRNA synthesis.
The overproduction of beta-amyloid (A beta) appears to be a primary cause of Alzheimer's disease (AD). A beta can be generated by proteolytic cleavage of precursor protein (beta APP) at beta- and gamma-secretase sites in both disease and normal cells. There is, however, no evidence that proteolytic processing of beta APP in sporadic AD-affected tissues differs qualitatively or quantitatively from that occurring in normal cells, and additional pathways for the enhanced production of A beta in sporadic AD which constitutes the majority of all AD cases should be considered. The major factor limiting the production of A beta in normal cells is cleavage at the alpha-secretase site within the A beta sequence. But, whereas the intact beta APP is a substrate for cleavage at the alpha-secretase site, the immediate precursor of A beta, 12-kDa C-terminal beta APP fragment, is not susceptible to the alpha-secretase cleavage but it can be cleaved by gamma-secretase thus generating A beta. Moreover, the gamma-secretase cleavage is not the rate-limiting step in the production of A beta. Therefore, the increase in production of the 12-kDa C-terminal beta APP fragment may be an efficient way to overproduce A beta. A mechanism for the generation of the 12-kDa fragment independently of beta APP is proposed. It postulates an additional step of amplification of mRNA, namely the antisense RNA-mediated generation of a truncated mRNA encoding 12-kDa C-terminal fragment. Initiation of translation at the first AUG in the truncated mRNA results in a polypeptide that is cleaved by gamma-secretase generating A beta. The proposed model makes several verifiable predictions and suggests new directions of experimentation that may lead to a better understanding of the mechanisms involved in AD.
Volloch
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Boston Biomedical Research Institute, MA 02114, USA.
D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D016372:RNA, Antisense / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D016372:RNA, Antisense; D012333:RNA, Messenger