Alzheimer’s disease (AD) is a devastating neurodegenerative condition with no known cure. While current therapies target late-stage amyloid formation and cholinergic tone, to date, these strategies have proven ineffective at preventing disease progression. The reasons for this may be varied, and could reflect late intervention, or, that earlier pathogenic mechanisms have been overlooked and permitted to accelerate the disease process. One such example would include synaptic pathology, the disease component strongly associated with cognitive impairment. Dysregulated Ca2+ homeostasis may be one of the critical factors driving synaptic dysfunction. One of the earliest pathophysiological indicators in mutant presenilin (PS) AD mice is increased intracellular Ca2+ signaling, predominantly through the ER-localized inositol triphosphate (IP3) and ryanodine receptors (RyR). In particular, the RyR-mediated Ca2+ upregulation within synaptic compartments is associated with altered synaptic homeostasis and network depression at early (presymptomatic) AD stages. Here, we offer an alternative approach to AD therapeutics by stabilizing early pathogenic mechanisms associated with synaptic abnormalities. We targeted the RyR as a means to prevent disease progression, and sub-chronically treated AD mouse models (4-weeks) with a novel formulation of the RyR inhibitor, dantrolene. Using 2-photon Ca2+ imaging and patch clamp recordings, we demonstrate that dantrolene treatment fully normalizes ER Ca2+ signaling within somatic and dendritic compartments in early and later-stage AD mice in hippocampal slices. Additionally, the elevated RyR2 levels in AD mice are restored to control levels with dantrolene treatment, as are synaptic transmission and synaptic plasticity. Aβ deposition within the cortex and hippocampus is also reduced in dantrolene-treated AD mice. In this study, we highlight the pivotal role of Ca2+ aberrations in AD, and propose a novel strategy to preserve synaptic function, and thereby cognitive function, in early AD patients.

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Objective Adipose stem cells (ASCs) have been shown in many preclinical studies to be potent suppressors of the immune system. Prior studies suggest that ASCs may promote cancer progression and wound healing. However, clinical studies investigating the effects of native, or fat‐grafted adipose tissue on cancer recurrence have generated mixed results. We investigated whether adipose content in reconstructive free flaps for oral squamous cell carcinoma (OSCC) is associated with disease recurrence and/or reduction in wound complications. Study Design Retrospective chart review. Setting Academic medical center. Methods We performed a review of 55 patients undergoing free flap reconstruction for OSCC over a 14‐month period. Using texture analysis software, we measured the relative free flap fat volume (FFFV) in postoperative computed tomography scans and compared fat volume with patient survival, recurrence, and wound healing complications. Results We report no difference in mean FFFV between patients with or without recurrence: 13.47 cm 3 in cancer‐free survivors and 17.99 cm 3 in cases that recurred ( p = .56). Two‐year recurrence‐free survival in patients with high and low FFFV was 61.0% and 59.1%, respectively ( p = .917). Although only 9 patients had wound healing complications, we found no trend in the incidence of wound healing complications between patients with high versus low FFFV. Conclusion FFFV is not associated with recurrence or wound healing in patients undergoing free flap reconstruction for OSCC, suggesting adipose content should not be of concern to the reconstructive surgeon.