Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly, with only palliative treatments available at this time. The AD brain contains extensive neuronal and synaptic loss, which are caused by the presence of extracellular amyloid plaques, mainly composed of the β-amyloid peptide (Aβ), and neurofibrillary tangles (NFTs), comprised of hyperphosphorylated tau (Querfurth and LaFerla). 95% of AD cases are sporadic, with no known genetic causes. Our understanding of why these patients develop the disease is poor but likely due to complex interactions between individual predisposing genetic traits and diverse factors, such as aging, sex hormones, cardiovascular disorders, stressful life events and apolipoprotein ε4 allele (Hoenicka, 2006).
One early event in AD is an increase in circulating glucocorticoids (GCs) (Davis et al., 1986b; de Leon et al., 1988; Masugi et al., 1989b; Miller et al., 1994; Swaab et al., 1994; Hartmann et al., 1997; Weiner et al., 1997; Swanwick et al., 1998a; Umegaki et al., 2000; Giubilei et al., 2001; Rasmuson et al., 2001; Sass et al., 2001; de Bruin et al., 2002; Armanini et al., 2003; Hatfield et al., 2004; Csernansky et al., 2006; Hoogendijk et al., 2006; Souza-Talarico et al., 2008; Wahbeh et al., 2008; Huang et al., 2009; Laske et al., 2009; Popp et al., 2009; Arsenault-Lapierre et al., 2010). The glucocorticoid response to stressful stimuli is regulated by the hypothalamic-pituitary-adrenal (HPA) axis, which triggers the adrenal cortex to release glucocorticoids (cortisol in primates, corticosterone in mice and rats). Glucocorticoids are steroid hormones that readily cross the blood-brain barrier and bind to low-affinity glucocorticoid receptors (GR) and high-affinity mineralocorticoid receptors (MR) (Reul and de Kloet, 1985). Activity of these receptors is necessary for normal cellular metabolic activity and crucial for many CNS functions, including learning and memory (Roozendaal, 2000). There is ample evidence implicating HPA-axis dysfunction in AD, reflected by markedly elevated basal levels of circulating cortisol, and a failure to show cortisol suppression following a dexamethasone challenge (Greenwald et al., 1986; Molchan et al., 1990; Nasman et al., 1995).
We previously showed that glucocorticoids drive the formation of AD hallmark pathologies – through increased production of the Aβ peptide, and increased accumulation of somatodendritic tau (Green et al., 2006), through agonism at the GR. Notably, GC’s increase steady-state levels of amyloid precursor protein (APP) and β-site APP cleaving enzyme (BACE1), and augment tau accumulation in the 3xTg-AD (Green et al., 2006). In addition, both stress and increased GC exposure induce cognitive impairment, trigger APP misprocessing, reduce Aβ clearance by decreased activity of insulin degrading enzyme and stimulate tau hyperphosphorylation (Li et al.; Kulstad et al., 2005; Jeong et al., 2006; Sotiropoulos et al., 2008; Catania et al., 2009), together demonstrating a key role for GC’s in the progression of AD pathology and cognitive decline.
Disease modification, through inhibition of Aβ generation, is the holy grail of AD therapeutics research. Aβ is sequentially cleaved from its parent protein APP, firstly by BACE 99 amino acids from the C-terminal of APP, and then by the γ-secretase complex, of which presenilin forms the catalytic core, which liberates Aβ from the membrane most commonly as a 40 or 42 amino acid peptide. Inhibition of either of these APP cleavages prevents Aβ generation. However, despite over 10 years of compound screening no effective inhibitor has been found which is bioactive in the brain, but also safe. Highly potent γ-secretase inhibitors have been developed, but have been shown to be toxic to neurons (Plant et al., 2003) as well as to promote skin cancer (Zhang et al., 2007) due to the extremely large list of substrates for the γ-secretase complex (McCarthy et al., 2009). Indeed, a recent phase III clinical trial by Lilly showed that patients on the drug actually declined faster then placebo, and showed the predicted increases in skin cancer. γ-secretase modulators have also been described, which alter the way that the complex cleaves APP, to generate shorter, less toxic, Aβ peptides. However, these modulators have low efficacy and have since failed in clinical trials. BACE is the primary target for blocking generation of Aβ and BACE inhibitors have also been developed. BACE has no other known function in the adult brain, and BACE knockout mice are perfectly viable (Roberds et al., 2001) with few obvious deficits. The large binding pocket of BACE combined with its membrane location have proved a challenge in designing effective inhibitors which can cross the blood brain barrier in sufficient concentrations to be useful, and no effective compounds to date have been fully developed.