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 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 wag 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.