Retinoic Acid-Elicited RARα/RXRα Signaling Attenuates Aβ Production by Directly Inhibiting γ-Secretase-Mediated Cleavage of Amyloid Precursor Protein

Abstract

Retinoic acid (RA)-elicited signaling has been shown to play critical roles in development, organogenesis, and the immune response. RA regulates expression of Alzheimer's disease (AD)-related genes and attenuates amyloid pathology in a transgenic mouse model. In this study, we investigated whether RA can suppress the production of amyloid-β (Aβ) through direct inhibition of γ-secretase activity. We report that RA treatment of cells results in significant inhibition of γ-secretase-mediated processing of the amyloid precursor protein C-terminal fragment APP-C99, compared with DMSO-treated controls. RA-elicited signaling was found to significantly increase accumulation of APP-C99 and decrease production of secreted Aβ40. In addition, RA-induced inhibition of γ-secretase activity was found to be mediated through significant activation of extracellular signal-regulated kinases (ERK1/2). Treatment of cells with the specific ERK inhibitor PD98059 completely abolished RA-mediated inhibition of γ-secretase. Consistent with these findings, RA was observed to inhibit secretase-mediated proteolysis of full-length APP. Finally, we have established that RA inhibits γ-secretase through nuclear retinoic acid receptor-α (RARα) and retinoid X receptor-α (RXRα). Our findings provide a new mechanistic explanation for the neuroprotective role of RA in AD pathology and add to the previous data showing the importance of RA signaling as a target for AD therapy.

Neuroprotection against Amyloid-β-Induced DNA Double-Strand Breaks Is Mediated by Multiple Retinoic Acid-Dependent Pathways

“…However, we suggest here that ADAM10 is implicated in RA neuroprotection against Aβ-induced DSBs, especially as the Presenilin-1 protein, corresponding in our experiments to the immature uncleaved form [42], and the BACE1 protein did not show an increase in expression. Furthermore, it was already shown that RA inhibits the γ-secretase, thus increasing APP [34]. Note that the increase of the 110 kDa APP signal suggests that, despite increased cleavage at the α-site, there is an enhanced APP expression due to the activated RAdependent metabolism.…”

“…Indeed, RA can increase, via the RARα receptor, the expression of ADAM10 (a disintegrin and metalloproteinase domain-containing protein 10), the major α-secretase [32], more than it increases the β-site cleaving enzyme BACE1, a β-secretase [33]. Furthermore, RA achieves a similar result by inhibiting the γ-secretase (or Presenilin-1) activity through activation of the Extracellular Signal-Regulated Kinase (ERK) 1/2 [34]. Thus, by changing the expression of enzymes of the amyloid cascade, RA might also prevent the formation of Aβ-induced DSBs and be a factor of neuroprotection against Aβ-induced DSBs and not just of DSB repair.…”

The Vitamin A Derivative All-Trans Retinoic Acid Repairs Amyloid-β-Induced Double-Strand Breaks in Neural Cells and in the Murine Neocortex

“…This effect is mediated by RA-responsive elements upstream of the ADAM10 coding region [ 30 , 31 ]. RA can also inhibit the γ -secretase activity through activation of the Extracellular Signal Regulated Kinase, ERK1/2 [ 32 ]. Secondly, vitamin A and its derivatives appear to inhibit A β oligomerisation in vitro , A β deposition, and tau phosphorylation in AD mouse models [ 33 ].…”

Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors

“…More precisely, only retinoic acid ␣ agonists (e.g., AM-580, Roche) reduced the number of A␤ plaques, whereas retinoic acid ␤ (e.g., CD-2019) or retinoic acid ␥ agonists (e.g., CD-437) had no effect on plaque load [420,421]. The A␤ production is attenuated by direct inhibition of ␥secretase-mediated cleavage of A␤PP [422]. Retinoic acid-elicited RAR␣/RXR␣ signaling attenuated the A␤ production by direct inhibition of ␥-secretasemediated cleavage of A␤PP [423].…”

“…The A␤ production is attenuated by direct inhibition of ␥secretase-mediated cleavage of A␤PP [422]. Retinoic acid-elicited RAR␣/RXR␣ signaling attenuated the A␤ production by direct inhibition of ␥-secretasemediated cleavage of A␤PP [423]. The retinoic acid-inducible gene-I (RIG-1) receptor is significantly elevated in the temporal cortex and plasma in patients with MCI [424].…”