β-amyloid 1-42 induces physiological transcriptional regulation of BACE1.
The pathogenesis of Alzheimer's disease (AD) is only partially understood. β-amyloid (Aβ) is physiologically generated by sequential cleavage of its precursor protein by the β- and the γ-secretase and it is normally disposed of. In Alzheimer's disease, Aβ is excessively produced or less dismissed, but the hypothesis on its physiological and pathological role are heterogeneous and often discordant. It has been described a positive feedback loop from the γ- to the β-secretase cleavages of Aβ precursor protein, which is activated by mutations of Presenilin 1 (PS1), the catalytic core of the γ-secretase. These findings show that Aβ precursor protein as well the activity of the γ-secretase are required to obtain the up-regulation of β-secretase which is induced by Presenilin 1 mutations. Then, Aβ 1-42 is the Aβ precursor protein derivative that up-regulates the expression of β-secretase, and c-jun N-terminal kinase (JNK)/c-Jun and ERK1/2 are involved. Here, we describe the activation of β-secretase and c-jun N-terminal kinase related proteins by monomeric Aβ 1-42, defining the conditions that most efficiently strike the described signaling without producing toxicity. Taken together these data imply that monomeric Aβ 1-42, at non-toxic concentrations and time frames, are able to induce a signaling pathway that leads to transcriptional activation of β-secretase.
Department of Internal Medicine and Medical Specialities, University of Genova, Genova, Italy.
Alessandra
A
Piccini
Roberta
R
Borghi
Michela
M
Guglielmotto
Elena
E
Tamagno
Gabriella
G
Cirmena
Anna
A
Garuti
Valeria
V
Pollero
Sergio
S
Cammarata
Michele
M
Fornaro
Massimo
M
Messa
Laura
L
Colombo
Mario
M
Salmona
George
G
Perry
Massimo
M
Tabaton
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D048670:MAP Kinase Kinase 4; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C022616:thiazolyl blue