Mifepristone Alters Amyloid Precursor Protein Processing to Preclude Amyloid Beta and Also Reduces Tau Pathology

Abstract

Background Increased circulating glucocorticoids are features of both aging and Alzheimer’s disease (AD), and increased glucocorticoids accelerate the accumulation of AD pathologies. Here we analyzed the effects of the glucocorticoid receptor antagonist mifepristone (RU-486) in the 3xTg-AD mouse model at an age where hippocampal damage leads to high circulating corticosterone levels. Methods The effects of mifepristone were investigated in 3xTg-AD mice using a combination of biochemical, histological and behaviour analyses. Results Mifepristone treatment rescues the pathologically-induced cognitive impairments and markedly reduces Aβ-load and levels, as well as tau pathologies. Analysis of APP processing revealed concomitant decreases in both APP C-terminal fragments C99 and C83 but the appearance of a larger 17-kDa C-terminal fragment. Hence, mifepristone induces a novel C-terminal cleavage of APP that prevents it being cleaved by α- or β- secretase, thereby precluding Aβ generation in the CNS; this cleavage and the production of the 17-kDa APP fragment was generated by a calcium-dependent cysteine protease. In addition, mifepristone treatment also reduced the phosphorylation and accumulation of tau, concomitant with reductions in p25. Notably, deficits in CREB signaling were restored with the treatment. Conclusions These preclinical results point to a potential therapeutic role for mifepristone as an effective treatment for AD and further highlight the impact the glucocorticoid system has as a regulator of Aβ generation.

Subchronic Glucocorticoid Receptor Inhibition Rescues Early Episodic Memory and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease

“…We can therefore attribute the observed memory deficit to a prolonged dysregulation of the HPA axis accompanied by APP misprocessing and not to acute changes in CORT levels induced by the design of the behavioral paradigm. A 4 days subchronic antagonism of GR was sufficient to have fully beneficial outcomes on memory impairment, corroborating a recent study in older 3xTg mice with more advanced AD pathology, which employed a chronic infusion of GR antagonist for 3 weeks (Baglietto-Vargas et al, 2013). This shorter daily treatment holds the advantage of minimizing the possible side effects of prolonged GR blockade (Morgan and Laufgraben, 2013).…”

“…Here, we provide solid evidence for an early impairment in episodic memory in 4-month old Tg2576 mice, correlating with early aggregation of Ab into oligomers, but before plaque formation (Hsiao et al, 1996;Mustafiz et al, 2011). To our knowledge, this is the first report of perturbation in this type of memory in the early phase of AD in AD mice, as few other studies tested this mnemonic deficit at more advanced stages of the pathology (Baglietto-Vargas et al, 2013;Davis et al, 2013;Good et al, 2007). In light of the impaired HPA axis feedback and the key role played by CORT in facilitating the consolidation of emotionally-charged memories (McGaugh and Roozendaal, 2002), it was crucial to monitor episodic memories in minimized stress conditions as presented here.…”

“…This issue will in the future benefit from the generation of double GR KO/Tg2576 mice. Nevertheless, other recently published data strongly argue for a specific GR-mediated beneficial effect of RU486 on the rescue of behavioral and biochemical phenotypes in another AD mouse model with more advanced neurodegeneration (Baglietto-Vargas et al, 2013). In a previous publication, we had reported a caspase-and calcineurin-dependent pathological mechanism leading to lower levels of synaptic AMPAR in the hippocampus of these early symptomatic mice (D'Amelio et al, 2011).…”

“…Both AD patients and AD mouse models display a dysregulated HPA axis, marked by a mild hypercortisolemia that is apparent early during the pathology (Csernansky et al, 2006;Elgh et al, 2006;Hebda-Bauer et al, 2013;Nasman et al, 1995;Rasmuson et al, 2001;Weiner et al, 1997). Increased CORT levels are sufficient to exacerbate Ab deposits, and a recent study suggested that antagonism of GR could prevent this effect (Baglietto-Vargas et al, 2013). Albeit this increasing evidence for a synergistic relationship between dysregulated HPA function and AD pathogenesis, its cellular underpinnings remain poorly understood.…”

Endogenous murine tau promotes neurofibrillary tangles in 3xTg-AD mice without affecting cognition

“…Morris water maze tests were conducted as described previously (Baglietto-Vargas et al, 2013;Billings et al, 2005;Medeiros et al, 2011). Mice were trained to swim to a 14 cm diameter circular Plexiglas platform submerged 1.5 cm beneath the surface of the water and invisible to the mice while swimming.…”