Ronal cell cultures exposed to dantrolene suggest that the reduced amyloid is likely mediated by reductions in APP phosphorylation and b- and c-secretase activity (25). However, using a different long-term oral dantrolene-treatment schedule (feeding twice/ week, 5 mg/kg, from 2? months of age), Zhang 1326631 et al., 2010 (2) describe an increase in amyloid load and neuronal atrophy. While the reasons for this discrepancy remain unclear, there are marked differences in the route and duration of dantrolene treatment, as well as the mouse models used and their age at the time of study which may affect outcome. Regardless of the outcomes, it is clearfrom these studies that manipulating RyR activity has profound effects on AD pathology across a range of symptoms and disease features. In this KDM5A-IN-1 series of experiments, we sought to determine if shorterterm, sub-chronic treatment (4 weeks) with the RyR inhibitor, dantrolene, is an effective strategy to normalize early pathogenic Ca2+ signaling and related synaptic transmission and plasticity deficits observed, as well as amyloid deposition, in the AD mice. By extension, we would expect similar effects in the human brain, and hope to prevent progression of AD pathology, rather than temporarily reduce symptoms. The origins of this approach are based on the knowledge that, in AD model systems, it is predominantly RyR-mediated responses that underlie aberrant intracellular Ca2+ signaling within synaptic compartments and contribute to altered synaptic homeostasis, and the observation that acute dantrolene in vitro can normalize ER Ca2+ signaling aberrations in presymptomatic AD mice [12]. More recently, and highly complementary to our findings, it has been demonstrated that extended chronic treatment (.10 months) with dantrolene reduced amyloid deposition and improved behavioral performance on learning and memory tasks [24]. Therefore, in this study, we treated AD and control mice at different stages of pathology (early, pre-histopathology without memory deficits, and mid-stage moderate plaque pathology coincident with onset of memory deficits) for a shorter duration with a nanocrystal formulation of dantrolene which crosses the blood-brain barrier [27]. We hypothesized that by normalizing an early pathogenic signaling cascade with far-reaching MedChemExpress 10236-47-2 physiological consequences, we would stabilize a host of physiological, histopathological, and synaptic deficits. We measured evoked Ca2+ responses via ER sources (IP3R and RyR) and from spike-evoked Ca2+ entry, electrical membrane properties, RyR isoform expression, synaptic transmission and plasticity properties, and density of amyloid deposition. In sum, we found this approach to be highly effective in early and mid-stages of the disease, and propose that it could serve as a new approach for the development of effective, disease modifying therapeutic strategies to treat AD, and possibly other Ca2+-regulated neurodegenerative diseases. An additional beneficial insight gleaned from this study is establishing the feed-forward association between ER Ca2+ upregulation and Ab deposition, as normalizing RyR-evoked Ca2+ signaling significantly reduced the deposition of Ab peptides and density of insoluble dense core plaques in mid-stage AD mice. It would be expected that earlier intervention would further reduce the extent of amyloid pathology and the related structural pathology associated with amyloid deposits. Dantrolene is an attractive drug to consider for AD treatment.Ronal cell cultures exposed to dantrolene suggest that the reduced amyloid is likely mediated by reductions in APP phosphorylation and b- and c-secretase activity (25). However, using a different long-term oral dantrolene-treatment schedule (feeding twice/ week, 5 mg/kg, from 2? months of age), Zhang 1326631 et al., 2010 (2) describe an increase in amyloid load and neuronal atrophy. While the reasons for this discrepancy remain unclear, there are marked differences in the route and duration of dantrolene treatment, as well as the mouse models used and their age at the time of study which may affect outcome. Regardless of the outcomes, it is clearfrom these studies that manipulating RyR activity has profound effects on AD pathology across a range of symptoms and disease features. In this series of experiments, we sought to determine if shorterterm, sub-chronic treatment (4 weeks) with the RyR inhibitor, dantrolene, is an effective strategy to normalize early pathogenic Ca2+ signaling and related synaptic transmission and plasticity deficits observed, as well as amyloid deposition, in the AD mice. By extension, we would expect similar effects in the human brain, and hope to prevent progression of AD pathology, rather than temporarily reduce symptoms. The origins of this approach are based on the knowledge that, in AD model systems, it is predominantly RyR-mediated responses that underlie aberrant intracellular Ca2+ signaling within synaptic compartments and contribute to altered synaptic homeostasis, and the observation that acute dantrolene in vitro can normalize ER Ca2+ signaling aberrations in presymptomatic AD mice [12]. More recently, and highly complementary to our findings, it has been demonstrated that extended chronic treatment (.10 months) with dantrolene reduced amyloid deposition and improved behavioral performance on learning and memory tasks [24]. Therefore, in this study, we treated AD and control mice at different stages of pathology (early, pre-histopathology without memory deficits, and mid-stage moderate plaque pathology coincident with onset of memory deficits) for a shorter duration with a nanocrystal formulation of dantrolene which crosses the blood-brain barrier [27]. We hypothesized that by normalizing an early pathogenic signaling cascade with far-reaching physiological consequences, we would stabilize a host of physiological, histopathological, and synaptic deficits. We measured evoked Ca2+ responses via ER sources (IP3R and RyR) and from spike-evoked Ca2+ entry, electrical membrane properties, RyR isoform expression, synaptic transmission and plasticity properties, and density of amyloid deposition. In sum, we found this approach to be highly effective in early and mid-stages of the disease, and propose that it could serve as a new approach for the development of effective, disease modifying therapeutic strategies to treat AD, and possibly other Ca2+-regulated neurodegenerative diseases. An additional beneficial insight gleaned from this study is establishing the feed-forward association between ER Ca2+ upregulation and Ab deposition, as normalizing RyR-evoked Ca2+ signaling significantly reduced the deposition of Ab peptides and density of insoluble dense core plaques in mid-stage AD mice. It would be expected that earlier intervention would further reduce the extent of amyloid pathology and the related structural pathology associated with amyloid deposits. Dantrolene is an attractive drug to consider for AD treatment.
