The close link between retinoid signalling and the α‐secretase ADAM10 and its potential for treating Alzheimer’s disease (Commentary on Jarvis et al.)

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease, affecting more than 20 million people worldwide. As amyloid β-peptide (Aβ) plays a crucial role in the pathogenesis of AD, reducing Aβ generation or clearing Aβ from the brain have been hypothesized to represent causal therapeutic strategies. Because α-secretases cleave amyloid precursor protein (APP) within the Aβ peptide domain and therefore preclude formation of Aβ, they have been considered promising candidates for such a therapy. Specifically, the disintegrin and metalloproteinase ADAM10 is known to be a physiologically relevant α-secretase for non-amyloidogenic processing of APP (Lammich et al., 1999). This pathway has also been shown to be neuroprotective. Thus, increased α-secretase activity prevents amyloid plaque formation and is beneficial for learning and memory in an AD transgenic mouse model (for recent reviews see Fahrenholz, 2007; Endres & Fahrenholz, 2010). Genetic, metabolic and dietary evidence has indicated the presence of a defective retinoid metabolism in AD (Goodman & Pardee, 2003). Recent studies demonstrated a close link between retinoid signalling and α-secretase activity. The ADAM10 promoter contains retinoid receptor binding sites. It has been found that retinoids induce expression of ADAM10 and α-secretase activity, via stimulation of retinoic acid receptors (RARs; Tippmann et al., 2009). RAR activation may therefore constitute a therapeutic target. Further evidence in support of this view is described in this issue of EJN in a study led by Jonathan Corcoran (Jarvis et al., 2010). These authors show that α-RAR agonists increase the expression of ADAM10 and prevent Aβ formation as well as Aβ-mediated neurodegeneration. Importantly, Jarvis et al. (2010) also demonstrate that RAR α-agonists pass the blood–brain barrier and stimulate the non-amyloidogenic pathway in the brain of AD transgenic mice. Further experiments will need to determine whether the compounds used in this study could serve as valuable lead compounds for the development of clinical treatment for AD. Because retinoids regulate several genes involved in cell proliferation and differentiation, potential complexities will have to be carefully considered. It is worth noting that the retinoid acitretin recently has been identified as an α-secretase activator (Tippmann et al., 2009). This compound is employed to treat psoriasis and is well tolerated for long-term treatment of patients. Presently, the significance of the proposed therapeutic mechanism of acicretin is being tested in a clinical AD trial. The close connection between retinoid signalling and ADAM10 has been extended to sirtuins. These are NAD-dependent deacetylases that have been reported to counter the effects of ageing on cell metabolism. The sirtuin SIRT1 directly activates transcription of the gene encoding the α-secretase ADAM10 (Donmez et al., 2010). This effect is due to deacetylation and co-activation of RAR-β. Upregulation of ADAM10 by SIRT1 activators via retinoid signalling may provide yet another way to stimulate non-amyloidogenic processing of APP.