Reelin and APP Cooperatively Modulate Dendritic Spine Formation In Vitro and In Vivo.

Amyloid precursor protein (APP) plays an important role in the pathogenesis of Alzheimer's disease (AD), but the normal function of APP at synapses is poorly understood. We and others have found that APP interacts with Reelin and that each protein is individually important for dendritic spine formation, which is associated with learning and memory, in vitro. However, whether Reelin acts through APP to modulate dendritic spine formation or synaptic function remains unknown. In the present study, we found that Reelin treatment significantly increased dendritic spine density and PSD-95 puncta number in primary hippocampal neurons. An examination of the molecular mechanisms by which Reelin regulates dendritic spinogenesis revealed that Reelin enhanced hippocampal dendritic spine formation in a Ras/ERK/CREB signaling-dependent manner. Interestingly, Reelin did not increase dendritic spine number in primary hippocampal neurons when APP expression was reduced or in vivo in APP knockout (KO) mice. Taken together, our data are the first to demonstrate that Reelin acts cooperatively with APP to modulate dendritic spine formation and suggest that normal APP function is critical for Reelin-mediated dendritic spinogenesis at synapses.

Opioid-free anesthesia for adenotonsillectomy in children.

INTRODUCTION: Opioids are administered during the intraoperative and postoperative periods in pediatric adenotonsillectomy and tonsillectomy. Non-opioid analgesics are often used as an analgesic during pediatric adenotonsillectomy and tonsillectomy. In this hypothesis generating study, we are evaluating safety and efficacy of stand-alone opioid analgesia for adenotonsillectomy and tonsillectomy. METHODS: This is a single-center retrospective chart review of patients ages 2 to 13 who underwent elective adenotonsillectomy and tonsillectomy. We used a convenience sampling method to select patients who received intraoperative intravenous fentanyl, acetaminophen, ibuprofen, or any combination thereof. The following outcomes were analyzed in this study: (i) the length of Post Anesthesia Care Unit stay, (ii) administration of postoperative opioids; (iii) postoperative opioid equivalents required; (iv) administration of postoperative non-opioid analgesics; and (v) inpatient admission from ED within 30 days. We used univariate analysis to compare the data points. RESULTS: We analyzed data from 323 patients who underwent adenotonsillectomy and tonsillectomy. The Post Anesthesia Care Unit length stay was similar for the intraoperative opioid-free and intraoperative opioid groups, 146.68 (±67.35) and 143.18 (±37.85) minutes, respectively (p = 0.586). Additionally, 102 patients (73.4%) in the intraoperative opioid-free group and 184 patients (83.2%) in the intraoperative opioid group did not receive any postoperative opioids (p = 0.033). The incidence of adverse events was similar between the intraoperative opioid-free and intraoperative opioid groups 3 (2.2%) and 5 (2.7%) respectively, p-value 0.749. A subgroup analysis comparing extracapsular 235 (72.8%) versus intracapsular 88 (27.2%) tonsillectomy yielded similar results. CONCLUSION: In this study, our data indicates that American Society of Anesthesiologists I- II pediatric patients undergoing adenotonsillectomy and tonsillectomy can be efficiently and safely managed with an opioid-free intraoperative and postoperative analgesic regimen. Due to the explained limitations, our study results should be interpreted cautiously.

Deficiency in LRP6-mediated Wnt signaling contributes to synaptic abnormalities and amyloid pathology in Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurological disorder characterized by synaptic loss and dementia. The low-density lipoprotein receptor-related protein 6 (LRP6) is an essential coreceptor for Wnt signaling, and its genetic variants have been linked to AD risk. Here we report that neuronal LRP6-mediated Wnt signaling is critical for synaptic function and cognition. Conditional deletion of Lrp6 gene in mouse forebrain neurons leads to age-dependent deficits in synaptic integrity and memory. Neuronal LRP6 deficiency in an amyloid mouse model also leads to exacerbated amyloid pathology due to increased APP processing to amyloid-ß. In humans, LRP6 and Wnt signaling are significantly downregulated in AD brains, likely by a mechanism that depends on amyloid-ß. Our results define a critical pathway in which decreased LRP6-mediated Wnt signaling, synaptic dysfunction, and elevated Aß synergistically accelerate AD progression and suggest that restoring LRP6-mediated Wnt signaling can be explored as a viable strategy for AD therapy.