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A mechanism for β‐amyloid overproduction in Alzheimer's disease: precursor‐independent generation of β‐amyloid via antisense RNA‐primed mRNA synthesis
Author(s) -
Volloch Vladimir
Publication year - 1996
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(96)00663-1
Subject(s) - amyloid precursor protein , cleavage (geology) , beta (programming language) , messenger rna , amyloid precursor protein secretase , microbiology and biotechnology , amyloid beta , alpha secretase , rna , biology , chemistry , protein precursor , biochemistry , enzyme , alzheimer's disease , gene , peptide , medicine , disease , paleontology , fracture (geology) , computer science , programming language
The overproduction of β‐amyloid (A β ) appears to be a primary cause of Alzheimer's disease (AD). A β can be generated by proteolytic cleavage of precursor protein ( β APP) at β‐ and γ‐secretase sites in both disease and normal cells. There is, however, no evidence that proteolytic processing of β 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 β in sporadic AD which constitutes the majority of all AD cases should be considered. The major factor limiting the production of A β in normal cells is cleavage at the α‐secretase site within the A β sequence. But, whereas the intact β APP is a substrate for cleavage at the α‐secretase site, the immediate precursor of A β , 12‐kDa C‐terminal β APP fragment, is not susceptible to the α‐secretase cleavage but it can be cleaved by γ‐secretase thus generating A β . Moreover, the γ‐secretase cleavage is not the rate‐limiting step in the production of A β . Therefore, the increase in production of the 12‐kDa C‐terminal β APP fragment may be an efficient way to overproduce A β . A mechanism for the generation of the 12‐kDa fragment independently of β 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 γ‐secretase generating A β . 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.