A mechanism for β‐amyloid overproduction in Alzheimer's disease: precursor‐independent generation of β‐amyloid via antisense RNA‐primed mRNA synthesis

FEBS Letters

Volloch, Vladimir¹ 

[1] Boston Biomedical Research Institute, 20 Staniford Street, Boston, MA 02114, USA

关键词: Alzheimer's disease;    β-Amyloid precursor protein (βAPP);    β-Amyloid (Aβ);    β-Amyloid overproduction;    Antisense RNA;    mRNA replication;   

DOI  :  10.1016/0014-5793(96)00663-1

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 (_βAPP) at β- and γ-secretase sites in both disease and normal cells. There is, however, no evidence that proteolytic processing of _βAPP 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 _βAPP is a substrate for cleavage at the α-secretase site, the immediate precursor of A_β, 12-kDa C-terminal _βAPP 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 _βAPP fragment may be an efficient way to overproduce A_β. A mechanism for the generation of the 12-kDa fragment independently of _βAPP 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.

【 授权许可】

Unknown