β-Amyloid 1-42 induces physiological transcriptional regulation of BACE1

J. Neurochem. (2012) 122, 10231031. Abstract The pathogenesis of Alzheimers disease (AD) is only partially understood. beta-amyloid (A beta) is physiologically generated by sequential cleavage of its precursor protein by the beta- and the ?-secretase and it is normally disposed of. In Alzheimers disease, A beta 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 ?- to the beta-secretase cleavages of A beta precursor protein, which is activated by mutations of Presenilin 1 (PS1), the catalytic core of the ?-secretase. These findings show that A beta precursor protein as well the activity of the ?-secretase are required to obtain the up-regulation of beta-secretase which is induced by Presenilin 1 mutations. Then, A beta 1-42 is the A beta precursor protein derivative that up-regulates the expression of beta-secretase, and c-jun N-terminal kinase (JNK)/c-Jun and ERK1/2 are involved. Here, we describe the activation of beta-secretase and c-jun N-terminal kinase related proteins by monomeric A beta 1-42, defining the conditions that most efficiently strike the described signaling without producing toxicity. Taken together these data imply that monomeric A beta 1-42, at non-toxic concentrations and time frames, are able to induce a signaling pathway that leads to transcriptional activation of beta-secretase.