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The treatment of ischemic strokes is limited to the prevention of cerebrovascular risk factors and to the modulation of the coagulation cascade during the acute phase. A new therapeutic strategy could be to preventively protect the brain against noxious biological reactions induced by cerebral ischemia such as oxidative stress and inflammation to minimize their neurological consequences. Here, we show that a peroxisome proliferator-activated receptor (PPAR-alpha) activator, fenofibrate, protects against cerebral injury by anti-oxidant and anti-inflammatory mechanisms. A 14 d preventive treatment with fenofibrate reduces susceptibility to stroke in apolipoprotein E-deficient mice as well as decreases cerebral infarct volume in C57BL/6 wild-type mice. The neuroprotective effect of fenofibrate is completely absent in PPAR-alpha-deficient mice, suggesting that PPAR-alpha activation is involved as a mechanism of the protection against cerebral injury. Furthermore, this neuroprotective effect appears independently of any improvement in plasma lipids or glycemia and is associated with (1) an improvement in middle cerebral artery sensitivity to endothelium-dependent relaxation unrelated to an increase in nitric oxide synthase (NOS) type III expression, (2) a decrease in cerebral oxidative stress depending on the increase in numerous antioxidant enzyme activities, and (3) the prevention of ischemia-induced expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in cerebral vessels without any change in NOS II expression. These data demonstrate that PPAR-alpha could be a new pharmacological target to preventively reduce the deleterious neurological consequences of stroke in mice and suggest that PPAR-alpha activators could preventively decrease the severity of stroke in humans.

Amyloid precursor protein (APP) metabolism is central to the pathogenesis of Alzheimer disease. We showed recently that the amyloid intracellular domain (AICD), which is released by ␥-secretase cleavage of APP C-terminal fragments (CTFs), is strongly increased in cells treated with alkalizing drugs (Vingtdeux, V., Hamdane, M., Bégard, S., Loyens, A., Delacourte, A., Beauvillain, J.-C., Buée, L., Marambaud, P., and Sergeant, N. Amyloid precursor protein (APP)3 metabolism is central to Alzheimer disease etiopathogenesis. Extracellular amyloid deposits, a neuropathological hallmark of Alzheimer disease, are composed of amyloid-␤ (A␤) peptides that derive from APP catabolism. APP is a type I transmembrane glycoprotein processed by an ␣-or a ␤-secretase to produce C-terminal fragments (CTFs) (for review, see Ref. 1). ␥-Secretase further processes APP-CTFs (2, 3), releasing A␤ from ␤-CTF and the amyloid intracellular domain (AICD or ⑀-CTF) from all APP-CTFs (2, 4 -8). Several lines of evidence suggest that AICD is a trans-regulating factor of gene expression (neprilysin, KAI1, APP, and glycogen synthase kinase-3␤) (9 -12). However, AICD is rapidly degraded and thus seldom detected (13). We showed recently that AICD is strongly increased upon treatment with alkalizing drugs, suggesting that the endosomal/lysosomal pathway regulates AICD degradation (14).The endosomal/lysosomal pathway is essential for A␤ production and APP catabolism. For instance, BACE-1 (beta-site APP-cleaving enzyme 1) resides within endosomes, and endocytosis of BACE-1 and APP is a prerequisite for generating A␤ (15-17). An acidic pH is necessary for optimal BACE-1 protease activity (18), and BACE-1 is degraded in lysosomes (19). The ␥-secretase activity has been localized at the endosomal/ lysosomal membrane (20 -23). Treatment with drugs that prevent endosomal/lysosomal acidification (24 -26) or deletion of the APP internalization motif (27, 28) dramatically reduces A␤ secretion.The endosomal/lysosomal system is likely to be altered in Alzheimer disease (for review, see Ref. 29). Several APP derivatives accumulate in multivesicular bodies (MVBs), in transgenic animal models of amyloidosis (30, 31), in Alzheimer disease (30), and in cell models (32). MVBs belong to the endocytic pathway (33); are at the crossroad of several cellular mechanisms such as membrane receptor recycling and protein degradation; and can release their intraluminal vesicles, known as exosomes (for review, see Refs. 34 -36). More recently, exosomes were demonstrated to contain A␤ peptides (37). Taken together, a growing body of evidence suggests that APP processing takes place mainly between the plasma membrane and late endosomal compartments such as multivesicular endosomes. Herein, we studied the localization of APP and its derivatives in SY5Y neuroblastoma cells stably overexpressing human APP and demonstrate that APP, APP-CTFs, and AICD accumulate in the luminal vesicles of multivesicular endosomes and are also found in exosomes.

PPARs (peroxisome-proliferator-activated receptors) are ligand-activated transcriptional factor receptors belonging to the so-called nuclear receptor family. The three isoforms of PPAR (alpha, beta/delta and gamma) are involved in regulation of lipid or glucose metabolism. Beyond metabolic effects, PPARalpha and PPARgamma activation also induces anti-inflammatory and antioxidant effects in different organs. These pleiotropic effects explain why PPARalpha or PPARgamma activation has been tested as a neuroprotective agent in cerebral ischaemia. Fibrates and other non-fibrate PPARalpha activators as well as thiazolidinediones and other non-thiazolidinedione PPARgamma agonists have been demonstrated to induce both preventive and acute neuroprotection. This neuroprotective effect involves both cerebral and vascular mechanisms. PPAR activation induces a decrease in neuronal death by prevention of oxidative or inflammatory mechanisms implicated in cerebral injury. PPARalpha activation induces also a vascular protection as demonstrated by prevention of post-ischaemic endothelial dysfunction. These vascular effects result from a decrease in oxidative stress and prevention of adhesion proteins, such as vascular cell adhesion molecule 1 or intercellular cell-adhesion molecule 1. Moreover, PPAR activation might be able to induce neurorepair and endothelium regeneration. Beyond neuroprotection in cerebral ischaemia, PPARs are also pertinent pharmacological targets to induce neuroprotection in chronic neurodegenerative diseases.

Plasma Aβ was associated with cognitive status and CSF biomarkers, suggesting the interest of plasma amyloid biomarkers for diagnosis purpose.

This article has an accompanying continuing medical education activity, also eligible for MOC credit, on page e19. Learning Objective: Upon completion of this CME activity successful learners will be able to (1) evaluate the probability of a venous thromboembolism (VTE) in patients with newly diagnosed pancreatic ductal adenocarcinoma (PDAC); (2) identify the risk factors for VTE in patients with PDAC; and (3) assess the impact of VTE on survival in patients with PDAC. Venous Thromboembolism and Pancreatic CancerThe BACAP-VTE Study : pancreatic cancer patients prospectively followed-up from time of enrollment until last visit or death 152 patients (20.79%) developed a VTE during a median follow-up of 19.3 months Patients developing VTE during follow-up had lower PFS (HR 1.74, 95%CI 1.19-2.54, P=.004) Patients developing VTE during follow-up had lower OS (HR 2.02, 95%CI 1.57-2.60, P<.001).

Accurate patient stratification into prognostic categories and targeting Amyotrophic Lateral Sclerosis (ALS)-associated pathways may pave the way for promising trials. We evaluated blood-based prognostic indicators using an array of pathological markers. Plasma samples were collected as part of a large, phase III clinical trial (Mitotarget/TRO19622) at months 1, 6, 12 and 18. The ALSFRS-r score was used as a proxy of disease progression to assess the predictive value of candidate biological indicators. First, established clinical predictors were evaluated in all 512 patients. Subsequently, pathologic markers, such as proxies of neuronal integrity (Neurofilament light chain and phosphorylated heavy chain), DNA oxidation (8-oxo-2′-desoxyguanosine), lipid peroxidation (4-hydroxy-2-nonenal, isoprostane), inflammation (interleukin-6) and iron status (ferritin, hepcidin, transferrin) were assessed in a subset of 109 patients that represented the whole cohort. Markers of neuronal integrity, DNA and lipid oxidation, as well as iron status at baseline are accurate predictors of disability at 18-month follow-up. The composite scores of these markers in association with established clinical predictors enable the accurate forecasting of functional decline. The identified four biomarkers are all closely associated with ‘ferroptosis’, a recently discovered form of programmed cell death with promising therapeutic targets. The predictive potential of these pathophysiology-based indicators may offer superior patient stratification for future trials, individualised patient care and resource allocation.

BackgroundGrowing body of evidence suggests that Parkinson’s disease (PD) is associated with oxidative damage via iron accumulation in the substantia nigra (SN). Low ceruloplasmin (CP)-ferroxidase activity has been identified in the SN and the cerebrospinal fluid (CSF) of patients with PD. The iron chelator, deferiprone, reduces the abnormally high levels of iron in the SN. In order to determine CP’s involvement in iron accumulation in SN and PD progression, we aim to compare the ability of iron chelation treatment to reducing both SN iron levels and motor handicap in PD patients according to the level of ceruloplasmin activity.MethodsWe used a moderate chelation protocol with deferiprone (DFP) based on a, 6-month delayed-start paradigm, randomized placebo controlled clinical trial in 40 PD patients. CP-ferroxidase activity was determined in blood and CSF together with the D544E gene polymorphism (rs701753). Iron levels were determined by R2* MRI sequence and the motor handicap by the UPDRS motor score.ResultsAfter 6 to 12 months of DFP treatment, greater reductions in SN iron levels and UPDRS motor scores were obtained in patients with higher serum and CSF levels of CP-ferroxidase activity. After 6 months of DFP treatment, the AT genotype group displayed greater reduction of iron level in the SN with greater CSF and serum levels of CP activity than the AA genotype group.ConclusionAlthough most of the DFP-treated patients displayed clinical and radiological improvements, those with the lower CP activity appeared to respond better to iron chelation. Larger RCTs are now needed to establish whether pharmacological modulation of CP activity could be an innovative neuroprotective strategy in PD.Trial registrationFAIR-PARK study (ClinicalTrials.gov reference: NCT00943748; French national reference number: 2008−006842−25). This study was approved by the French Drug Agency (ANSM) and the local institutional review board (“Comité de Protection des Personnes of Lille”).Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-015-0331-3) contains supplementary material, which is available to authorized users.