Glial Sphingosine-Mediated Epigenetic Regulation Stabilizes Synaptic Function in Drosophila Models of Alzheimer's Disease.

Destabilization of neural activity caused by failures of homeostatic regulation has been hypothesized to drive the progression of Alzheimer's Disease (AD). However, the underpinning mechanisms that connect synaptic homeostasis and the disease etiology are yet to be fully understood. Here, we demonstrated that neuronal overexpression of amyloid ß (Aß) causes abnormal histone acetylation in peripheral glia and completely blocks presynaptic homeostatic potentiation (PHP) at the neuromuscular junction in Drosophila The synaptic deficits caused by Aß overexpression in motoneurons are associated with motor function impairment at the adult stage. Moreover, we found that a sphingosine analog drug, Fingolimod, ameliorates synaptic homeostatic plasticity impairment, abnormal glial histone acetylation, and motor behavior defects in the Aß models. We further demonstrated that perineurial glial sphingosine kinase 2 (Sk2) is not only required for PHP, but also plays a beneficial role in modulating PHP in the Aß models. Glial overexpression of Sk2 rescues PHP, glial histone acetylation, and motor function deficits that are associated with Aß in Drosophila Finally, we showed that glial overexpression of Sk2 restores PHP and glial histone acetylation in a genetic loss-of-function mutant of the Spt-Ada-Gcn5 Acetyltransferase complex, strongly suggesting that Sk2 modulates PHP through epigenetic regulation. Both male and female animals were used in the experiments and analyses in this study. Collectively, we provided genetic evidence demonstrating that abnormal glial epigenetic alterations in Aß models in Drosophila are associated with the impairment of PHP and that the sphingosine signaling pathway displays protective activities in stabilizing synaptic physiology.SIGNIFICANCE STATEMENT Fingolimod, an oral drug to treat multiple sclerosis, is phosphorylated by sphingosine kinases to generate its active form. It is known that Fingolimod enhances the cognitive function in mouse models of Alzheimer's disease (AD), but the role of sphingosine kinases in AD is not clear. We bridge this knowledge gap by demonstrating the relationship between impaired homeostatic plasticity and AD. We show that sphingosine kinase 2 (Sk2) in glial cells is necessary for homeostatic plasticity and that glial Sk2-mediated epigenetic signaling has a protective role in synapse stabilization. Our findings demonstrate the potential of the glial sphingosine signaling as a key player in glia-neuron interactions during homeostatic plasticity, suggesting it could be a promising target for sustaining synaptic function in AD.

Dysregulated glial genes in Alzheimer's disease are essential for homeostatic plasticity: Evidence from integrative epigenetic and single cell analyses.

Synaptic homeostatic plasticity is a foundational regulatory mechanism that maintains the stability of synaptic and neural functions within the nervous system. Impairment of homeostatic regulation has been linked to synapse destabilization during the progression of Alzheimer's disease (AD). Recent epigenetic and transcriptomic characterizations of the nervous system have revealed intricate molecular details about the aging brain and the pathogenesis of neurodegenerative diseases. Yet, how abnormal epigenetic and transcriptomic alterations in different cell types in AD affect synaptic homeostatic plasticity remains to be elucidated. Various glial cell types play critical roles in modulating synaptic functions both during the aging process and in the context of AD. Here, we investigated the impact of glial dysregulation of histone acetylation and transcriptome in AD on synaptic homeostatic plasticity, using computational analysis combined with electrophysiological methods in Drosophila. By integrating snRNA-seq and H3K9ac ChIP-seq data from the same AD patient cohort, we pinpointed cell type-specific signature genes that were transcriptionally altered by histone acetylation. We subsequently investigated the role of these glial genes in regulating presynaptic homeostatic potentiation in Drosophila. Remarkably, nine glial-specific genes, which were identified through our computational method as targets of H3K9ac and transcriptional dysregulation, were found to be crucial for the regulation of synaptic homeostatic plasticity in Drosophila. Our genetic evidence connects abnormal glial transcriptomic changes in AD with the impairment of homeostatic plasticity in the nervous system. In summary, our integrative computational and genetic studies highlight specific glial genes as potential key players in the homeostatic imbalance observed in AD.

Impact of Enteral Albuterol on Bradycardic Events After Acute Cervical Spinal Cord Injury.

BACKGROUND: Acute cervical spinal cord injury (ACSCI) is commonly complicated by spinal shock, resulting in hemodynamic instability characterized by bradycardia and hypotension that can have fatal consequences. Current guidelines recommend the use of intravenous beta and dopamine agonists, such as norepinephrine and dopamine, respectively. We sought to determine whether enteral albuterol would be a safe and feasible treatment for bradycardia without an increase in the occurrence of known side effects of albuterol in patients with ACSCI. METHODS: A retrospective review of patients with ACSCI admitted to an intensive care unit at a level I trauma center and treated with enteral albuterol was conducted. Patients were excluded for the following reasons: pure beta blocker use prior to injury, concurrent use of pacemaker, age of less than 18 years, or age more than 75 years. As part of the standard of care, all patients underwent mean arterial pressure (MAP) augmentation to reach a goal of greater than 85 mm Hg during the first 7 days post injury. All eligible patient charts were reviewed for demographic characteristics, daily minimum and maximum heart rate and MAP, and concomitant vasoactive medication use. Bradycardia and tachycardia were defined as heart rate less than 60 beats per minute (bpm) and greater than 100 bpm, respectively. Factors found to be associated with bradycardia on univariate analysis were entered into a multivariable generalized estimating equation analysis to determine factors independently associated with bradycardia during the study period. RESULTS: There were 58 patients with cervical ASCI (age 45 ± 18 years, 76% men) admitted between January 1, 2016, and December 31, 2017, that met the study criteria. The mean time to initiation of albuterol was 1.5 ± 1.7 days post injury, with a duration of 9.3 ± 4.5 days and a mean daily dosage of 7.8 ± 4.5 mg. Bradycardia was observed in 136 of 766 patient days (17%). There were a few episodes of hyperglycemia (1%) and tachycardia (3%), but no episodes of hypokalemia. In a multivariable analysis, female sex (P = 0.006) and American Spinal Cord Injury Association grade A, B, or C (P < 0.001) were associated with a higher risk of developing bradycardia, whereas dosage of albuterol (P = 0.009) and norepinephrine use (P = 0.008) were associated with a lower risk of developing bradycardia. CONCLUSIONS: Albuterol administration in ASCI is a safe and feasible treatment for bradycardia, given that no significant side effects, such as hyperglycemia, hypokalemia, or tachycardia, were observed. The administration of enteral albuterol was well tolerated and, in a dose-dependent manner, associated with a lower occurrence of bradycardia. Further prospective trials for the use of enteral albuterol after SCI are warranted.