Cooperative Therapeutic Action of Retinoic Acid Receptor and Retinoid X Receptor Agonists in a Mouse Model of Alzheimer's Disease

Abstract

Abstract. Alzheimer's disease (AD) is a neurodegenerative process involving amyloid-␤ (A␤) peptide deposition, neuroinflammation, and progressive memory loss. Here, we evaluated whether oral administration of retinoic acid receptor (RAR)␣,␤ agonist Am80 (tamibarotene) or specific retinoid X receptor (RXR) pan agonist HX630 or their combination could improve deficits in an AD model, 8.5-month-old amyloid-␤ protein precursor 23 (A␤PP23) mice. Co-administration of Am80 (0.5 mg/kg) and HX630 (5 mg/kg) for 17 days significantly improved memory deficits (Morris water maze) in A␤PP23 mice, whereas administration of either agent alone produced no effect. Only co-administration significantly reduced the level of insoluble A␤ peptide in the brain. These results thus indicate that effective memory improvement via reduction of insoluble A␤ peptide in 8.5-month-old A␤PP23 mice requires co-activation of RAR␣,␤ and RXRs. RAR␣-positive microglia accumulated A␤ plaques in the A␤PP23 mice. Rat primary microglia co-treated with Am80/HX630 showed increased degradation activity towards 125 I-labeled oligomeric A␤ 1-42 peptide in an insulin-degrading enzyme (IDE)-dependent manner. The co-administration increased mRNA for IDE and membrane-associated IDE protein in vivo, suggesting that IDE contributes to A␤ clearance in Am80/HX630-treated A␤PP23 mice. Am80/HX630 also increased IL-4R␣ expression in microglial MG5 cells. The improvement in memory of Am80/HX630-treated A␤PP23 mice was correlated with the levels and signaling of hippocampal interleukin-4 (IL-4). Therefore, Am80/HX630 may promote differentiation of IL-4-responsive M2-like microglia and increase their activity for clearance of oligomeric A␤ peptides by restoring impaired IL-4 signaling in A␤PP23 mice. Combination treatment with RAR and RXR agonists may be an effective approach for AD therapy.

Marginal Vitamin A Deficiency Exacerbates Memory Deficits Following A?1-42 Injection in Rats

“…In addition, a positive correlation was observed between RARβ and IDE in the current study. This result supports a recent study reporting that RARα and RARβ agonists enhanced the expression of IDE [20]. Moreover, we found that RARα and RARγ were negatively correlated with IDE, which is inconsistent with a previous in vitro study showing that RA-elicited RARα induced IDE expression [46].…”

“…ADAM10, the central component of α-secretase, was identified as a key molecule in RA-mediated anti-AD mechanisms [45]. In addition, RA can increase Aβ clearance by enhancing the expression of the Aβ-degrading enzyme IDE [20, 46]. Moreover, the IDE gene contains a RARE in its promoter region [41].…”

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

“…Furthermore, in the short time, RA can repair DSBs and appears even to increase viability in the cortex of young and to a lesser extent of aged mice. The fact that RA is repairing DSBs as Am80 and trichostatin A and that both of them alter memorization [ 49 , 50 ] suggests a similar role for RA. We make the hypothesis that whereas A β produces DSBs, RA results in targeted error-prone repair of the subset of DNA regions with RA-dependent gene expression, involved in particular in neuronal or synaptic maintenance [ 23 ].…”

Optic nerve injury upregulates retinoic acid signaling in the adult frog visual system

“…It has also recently been implicated in the control of rhythms within the brain (Ransom et al, 2014). In addition, alterations in the expression of some of the components of RA signaling may contribute to the pathophysiology of various neurodegenerative diseases including ALS (Jokic et al, 2007; Kolarcik and Bowser, 2012) and Alzheimer's disease (Corcoran et al, 2004; Kawahara et al, 2014). …”