The Spared Nerve Injury (SNI) Model of Induced Mechanical Allodynia in Mice

Peripheral neuropathic pain is a severe chronic pain condition which may result from trauma to sensory nerves in the peripheral nervous system. The spared nerve injury (SNI) model induces symptoms of neuropathic pain such as mechanical allodynia i.e. pain due to tactile stimuli that do not normally provoke a painful response [1]

An Endocytic Pathway Essential for Renal Uptake and Activation of the Steroid 25-(OH) Vitamin D3

AbstractSteroid hormones may enter cells by diffusion through the plasma membrane. However, we demonstrate here that some steroid hormones are taken up by receptor-mediated endocytosis of steroid-carrier complexes. We show that 25-(OH) vitamin D3 in complex with its plasma carrier, the vitamin D–binding protein, is filtered through the glomerulus and reabsorbed in the proximal tubules by the endocytic receptor megalin. Endocytosis is required to preserve 25-(OH) vitamin D3 and to deliver to the cells the precursor for generation of 1,25-(OH)2 vitamin D3, a regulator of the calcium metabolism. Megalin−/− mice are unable to retrieve the steroid from the glomerular filtrate and develop vitamin D deficiency and bone disease

SorLA Controls Neurotrophic Activity by Sorting of GDNF and Its Receptors GFR alpha 1 and RET

Peer reviewe

ApoB100-LDL Acts as a Metabolic Signal from Liver to Peripheral Fat Causing Inhibition of Lipolysis in Adipocytes

International audienceBACKGROUND: Free fatty acids released from adipose tissue affect the synthesis of apolipoprotein B-containing lipoproteins and glucose metabolism in the liver. Whether there also exists a reciprocal metabolic arm affecting energy metabolism in white adipose tissue is unknown. METHODS AND FINDINGS: We investigated the effects of apoB-containing lipoproteins on catecholamine-induced lipolysis in adipocytes from subcutaneous fat cells of obese but otherwise healthy men, fat pads from mice with plasma lipoproteins containing high or intermediate levels of apoB100 or no apoB100, primary cultured adipocytes, and 3T3-L1 cells. In subcutaneous fat cells, the rate of lipolysis was inversely related to plasma apoB levels. In human primary adipocytes, LDL inhibited lipolysis in a concentration-dependent fashion. In contrast, VLDL had no effect. Lipolysis was increased in fat pads from mice lacking plasma apoB100, reduced in apoB100-only mice, and intermediate in wild-type mice. Mice lacking apoB100 also had higher oxygen consumption and lipid oxidation. In 3T3-L1 cells, apoB100-containing lipoproteins inhibited lipolysis in a dose-dependent fashion, but lipoproteins containing apoB48 had no effect. ApoB100-LDL mediated inhibition of lipolysis was abolished in fat pads of mice deficient in the LDL receptor (Ldlr(-/-)Apob(100/100)). CONCLUSIONS: Our results show that the binding of apoB100-LDL to adipocytes via the LDL receptor inhibits intracellular noradrenaline-induced lipolysis in adipocytes. Thus, apoB100-LDL is a novel signaling molecule from the liver to peripheral fat deposits that may be an important link between atherogenic dyslipidemias and facets of the metabolic syndrome

Preservation of cortical sortilin protein levels in MCI and Alzheimer\u27s disease

The nerve growth factor (NGF) precursor protein proNGF is the predominant NGF moiety found in the human neocortex and exhibits pro-apoptotic properties when bound to the p75NTR neurotrophin receptor in the presence of sortilin, a Vps10p domain trafficking protein. Recently studies have shown that proNGF levels increase in the cortex of people who died with early stage Alzheimer\u27s disease (AD) or with mild cognitive impairment (MCI), a putative prodromal AD stage. In contrast, cortical levels of the high-affinity, pro-survival NGF receptor TrkA are reduced in AD despite stable levels of p75NTR. These data suggest a stoichiometric shift in proNGF and its receptors which favors proNGF binding of p75NTR. Whether cortical levels of sortilin are altered during the progression of AD remains unknown. Therefore, we measured sortilin protein levels in postmortem superior frontal and superior temporal cortical tissues derived from Religious Orders Study subjects clinically diagnosed antemortem with no cognitive impairment (NCI), MCI or AD. No changes in frontal or temporal cortical sortilin protein levels occurred across the clinical groups. There was no association between sortilin levels and antemortem cognitive test scores. However, there was a positive association between temporal cortex sortilin levels and severity of neuropathology by Braak and NIA-Reagan diagnoses. The stability of cortical sortilin levels in the face of stable p75NTR, increased proNGF, and reduced TrkA levels may favor pro-apoptotic proNGF:p75NTR:sortilin trimeric interactions within the cortex during the earliest stages of AD. These findings are relevant to the development of NGF drug therapy for the treatment of dementia. © 2010 Elsevier Ireland Ltd. All rights reserved