Translation of the alzheimer amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5'-untranslated region sequences.
The amyloid precursor protein (APP) has been associated with Alzheimer's disease (AD) because APP is processed into the beta-peptide that accumulates in amyloid plaques, and APP gene mutations can cause early onset AD. Inflammation is also associated with AD as exemplified by increased expression of interleukin-1 (IL-1) in microglia in affected areas of the AD brain. Here we demonstrate that IL-1alpha and IL-1beta increase APP synthesis by up to 6-fold in primary human astrocytes and by 15-fold in human astrocytoma cells without changing the steady-state levels of APP mRNA. A 90-nucleotide sequence in the APP gene 5'-untranslated region (5'-UTR) conferred translational regulation by IL-1alpha and IL-1beta to a chloramphenicol acetyltransferase (CAT) reporter gene. Steady-state levels of transfected APP(5'-UTR)/CAT mRNAs were unchanged, whereas both base-line and IL-1-dependent CAT protein synthesis were increased. This APP mRNA translational enhancer maps from +55 to +144 nucleotides from the 5'-cap site and is homologous to related translational control elements in the 5'-UTR of the light and and heavy ferritin genes. Enhanced translation of APP mRNA provides a mechanism by which IL-1 influences the pathogenesis of AD.
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. Rogers@calvin.bwh.harvard.edu
J T
JT
Rogers
L M
LM
Leiter
J
J
McPhee
C M
CM
Cahill
S S
SS
Zhan
H
H
Potter
L N
LN
Nilsson
D000544:Alzheimer Disease; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D001253:Astrocytes; D001483:Base Sequence; D002478:Cells, Cultured; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation
D016564:Amyloid beta-Protein Precursor; D007375:Interleukin-1; D012333:RNA, Messenger