Mediator: the missing link in amyloid precursor protein nuclear signalling.

the amyloid cascade hypothesis—in which the age-dependent accumulation of the amyloid β-peptide (aβ) is proposed to be the trigger for alzheimer disease—has provided a huge impetus for research into disease mechanisms and contributed to the focusing of research on to alzheimer disease therapeutics. aβ itself is derived from the transmembrane amyloid precursor protein (app), the gene for which was the first to be linked with early onset alzheimer disease exactly 20 years ago (goate et al, 1991). Most subsequent therapeutic strategies have focused on modifying the formation, aggregation or removal of aβ. yet, two decades on, treatments remain limited and they are palliative, rather than curative for the disease. this suggests a missing link in the chain from disease initiation to cognitive decline and death. the focus on amyloid accumulation has therefore detracted from attempts to understand the normal functions of app. it might be that a loss of normal app metabolism and physio logy, as much as a gain in aβ toxicity, could contribute to the development of alzheimer disease and hence provide new approaches to therapy. aβ is only one of several metabolites of app that result from the actions of a set of proteases collectively referred to as secretases, which comprise the diseasepromoting βand γ-secretases (generating aβ), as well as the neuro protective (nonamyloido genic) α-secretase. these produce the soluble ectodomains sapp-β and -α, respectively, and a cyto plasmic fragment of 50–59 amino acids known as the app intracellular domain (aicD), all of which are fundamental to understanding the pathological effects of app dys regulation. However, theories about the role and mechanism of action of aicD have been controversial. aicD was originally suggested to function in transcriptional activation ana logously to the Notch intracellular domain, but the detection of aicD has been problematic, in part because of its rapid turnover. However, a consensus is emerging that aicD is formed and translocated to the nucleus in a retrograde manner, predominantly in a β-secretase-dependent manner, which involves a lipid-raftmediated, endosomal processing pathway (goodger et al, 2009; Belyaev et al, 2010). Several target genes have been proposed for aicD, but the best characterized is the neprilysin (NEP) gene that encodes a metallo protease that is itself involved in aβ degradation (pardossi-piquard et al, 2005; Belyaev et al, 2009). We have further proposed that neuronal specificity is imposed on this gene-regulatory mechanism by the preferential involvement of the 695 neuronal isoform of app, when compared with the ubiquitously expressed isoforms (app751 and app770) (Belyaev et al, 2010). general acceptance of aicD as a transcriptional regulator has foundered, however, owing to the lack of a more detailed mechanistic understanding. although we have shown a direct interaction between aicD and the NEp promoter (Belyaev et al, 2009, 2010), a more specific target within the general transcriptional apparatus has been lacking, as well as validation of a subset of aicD-responsive genes. the missing link seems to be the MED12 protein (Xu et al, 2011), which forms part of Mediator—a large protein complex of 30 subunits that transduces signals from specific transcription factors to rNa polymerase ii (pol ii). although the Mediator complex seems to be a requirement for transcription of most, if not all, eukaryotic pol ii promoters, indivi dual subunits are recruited to control specific transcriptional programmes, usually leading to transcriptional activation. in this context, MED12 is particularly important in relation to the nervous system, as it was previously implicated in neuronal development and cognitive impairment (Wang et al, 2006; clark et al, 2009). Xu et al (2011) have now identified MED12 as a protein that interacts with the carboxy-terminal tail of app family members, by using a yeast two-hybrid screen to map the interaction region to a specific pQL domain on MED12. two proteins that have been previously implicated in aicDdependent gene regulation—Fe65 and tip60—immunoprecipitated with MED12, but only in the presence of co-expressed aicD. Furthermore, aicD was shown to recruit the Mediator complex to aicDresponsive promoters, depending on the presence of MED12. in addition to NEP, several other genes were confirmed as being MED12/aicDdependent including aquaporin 1—previously identified by Huysseune et al (2009)—fibronectin 1 and microtubuleassociated monooxygenase (MICAL2). Of the many Mediator subunits, MED12 seems to be specifically linked to neural development and disease; it provides a mechanistic route through its intracellular domain for the involvement of app in gene regulation. given that mutations in MED12 lead to cognitive and behavioural dysfunction in humans, Xu et al (2011) speculate that polymorphisms in MED12 might also contribute to the development of alzheimer disease. it is our view that a fuller knowledge and validation of the genes regulated by aicD might open up new therapeutic avenues in alzheimer research. Furthermore, delineating the fine detail of the cellular site of production of aicD, its neuronal Mediator: the missing link in amyloid precursor protein nuclear signalling