Although glucose-sensing neurons were discovered more than 50 years ago, the physiological role of glucose sensing in metazoans remains unclear. Here, we identify a pair of glucose-sensing neurons (dubbed CN neurons) in the Drosophila brain with bifurcating axons whereby one axon branch projects to insulin-producing cells (IPCs) to trigger the release of Drosophila insulin-like peptide 2 (dilp2), and the other one extends to adipokinetic hormone (AKH)-producing cells to inhibit the secretion of AKH, fly's analog of glucagon. These axonal branches undergo synaptic remodeling in response to changes in their internal energy status. Silencing of CN neurons largely disabled IPCs' response to glucose and dilp2 secretion, and disinhibited AKH secretion in corpora cardiaca (CC), and caused hyperglycemia, a hallmark feature of diabetes mellitus. We propose that CN neurons maintain glucose homeostasis by promoting the secretion of dilp2 and suppressing the release of AKH when hemolymph glucose levels are high.Glucose-sensing neurons respond to glucose or its metabolite that act as a signaling cue to regulate their neuronal activity. According to the glucostatic hypothesis proposed in 1953, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

In Alzheimer's disease (AD), neurodegenerative signals such as amyloid-beta (Aβ) and the precursors of neurotrophins, outbalance neurotrophic signals, causing synaptic dysfunction and neurodegeneration. The neurotrophin receptor p75 (p75NTR) is a receptor of Aβ and mediates Aβ-induced neurodegenerative signals. The shedding of its ectodomain from the cell surface is physiologically regulated; however, the function of the diffusible p75NTR ectodomain (p75ECD) after shedding remains largely not known. Here, we show that p75ECD levels in cerebrospinal fluid and in the brains of Alzheimer's patients and amyloid-beta precursor protein (APP)/PS1 transgenic mice were significantly reduced, due to inhibition of the sheddase-tumor necrosis factor-alpha-converting enzyme by Aβ. Restoration of p75ECD to the normal level by brain delivery of the gene encoding human p75ECD before or after Aβ deposition in the brain of APP/PS1 mice reversed the behavioral deficits and AD-type pathologies, such as Aβ deposit, apoptotic events, neuroinflammation, Tau phosphorylation and loss of dendritic spine, neuronal structures and synaptic proteins. Furthermore, p75ECD can also reduce amyloidogenesis by suppressing β-secretase expression and activities. Our data demonstrate that p75ECD is a physiologically neuroprotective molecule against Aβ toxicity and would be a novel therapeutic target and biomarker for AD.

Sortilin, a Golgi sorting protein and a member of the VPS10P family, is the co-receptor for proneurotrophins, regulates protein trafficking, targets proteins to lysosomes, and regulates low density lipoprotein metabolism. The aim of this study was to investigate the expression and regulation of sortilin in Alzheimer's disease (AD). A significantly increased level of sortilin was found in human AD brain and in the brains of 6-month-old swedish-amyloid precursor protein/PS1dE9 transgenic mice. Ab 42 enhanced the protein and mRNA expression levels of sortilin in a dose-and time-dependent manner in SH-SY5Y cells, but had no effect on sorLA. In addition, proBDNF also significantly increased the protein and mRNA expression of sortilin in these cells. Abbreviations used: AD, Alzheimer's disease; APP, amyloid precursor protein; Ab, amyloid-b protein; BACE1, b-site APP-cleaving enzyme 1; BDNF, brain-derived neurotrophic factor; MTT, methyl thiazol tetrazolium bromide; PBS, phosphate buffer saline; RIPA, radio immune precipitation assay.

The processing of Amyloid precursor protein (APP) is multifaceted, comprising of protein transport, internalization and sequential proteolysis. However, the exact mechanism of APP intracellular trafficking and distribution remains unclear. To determine the interaction between sortilin and APP and the effect of sortilin on APP trafficking and processing, we studied the binding site and its function by mapping experiments, colocalization, coimmunoprecipitation and sucrose gradient fractionation. We identified for the first time that sortilin interacts with APP at both N- and C-terminal regions. The sortilin-FLVHRY (residues 787–792) and APP-NPTYKFFE (residues 759–766) motifs are crucial for the C-terminal interaction. We also found that lack of the FLVHRY motif reduces APP lysosomal targeting and increases APP distribution in lipid rafts in co-transfected HEK293 cells. These results are consistent with our in vivo data where sortilin knockout mice showed a decrease of APP lysosomal distribution and an increase of APP in lipid rafts. We further confirmed that overexpression of sortilin-FLVHRY mutants failed to rescue the lysosomal degradation of APP. Thus, our data suggests that sortilin is implicated in APP lysosomal and lipid raft targeting via its carboxyl-terminal F/YXXXXF/Y motif. Our study provides new molecular insights into APP trafficking and processing.