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Elevated amyloid-beta peptide (A beta) in brain contributes to Alzheimer's disease (AD) pathogenesis. We demonstrated the presence of exosome-associated A beta in the cerebrospinal fluid (CSF) of cynomolgus monkeys and APP transgenic mice. The levels of exosome-associated A beta notably decreased in the CSF of aging animals. We also determined that neuronal exosomes, but not glial exosomes, had abundant glycosphingolipids and could capture A beta. Infusion of neuronal exosomes into brains of APP transgenic mice decreased A beta and amyloid depositions, similarly to what reported previously on neuroblastoma-derived exosomes. These findings highlight the role of neuronal exosomes in A beta clearance, and suggest that their downregulation might relate to Ab accumulation and, ultimately, the development of AD pathology. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Elevated amyloid-beta peptide (A beta) in brain contributes to Alzheimer's disease (AD) pathogenesis. We demonstrated the presence of exosome-associated A beta in the cerebrospinal fluid (CSF) of cynomolgus monkeys and APP transgenic mice. The levels of exosome-associated A beta notably decreased in the CSF of aging animals. We also determined that neuronal exosomes, but not glial exosomes, had abundant glycosphingolipids and could capture A beta. Infusion of neuronal exosomes into brains of APP transgenic mice decreased A beta and amyloid depositions, similarly to what reported previously on neuroblastoma-derived exosomes. These findings highlight the role of neuronal exosomes in A beta clearance, and suggest that their downregulation might relate to Ab accumulation and, ultimately, the development of AD pathology. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Inflammatory cytokines are implicated in the neurodevelopmental hypothesis for schizophrenia. Based on this hypothesis, we studied the establishment of rodent models for schizophrenia by subcutaneously challenging rat or mouse neonates with various cytokines. Because of the physical and behavioral difference between animal species; however, it is difficult to fully evaluate the appropriateness of rodent models. To overcome this problem, we attempted to establish a non-human primate model of schizophrenia. We subcutaneously injected epidermal growth factor (EGF: 0.3 mg/kg/day) to 3 male neonatal cynomolgus monkeys for a total of 7 or 9 days from 14 days of age. During the following 4 or 5 years, no abnormal behaviors were observed in these monkeys treated with EGF; however, at the age of 6 years, 1 monkey exhibited abnormal behavioral traits: stereotypic movement, vocalization, alert motion, and self injury. It was noteworthy that the monkey often showed agitation and clapped its hands over its eyes and bit his hands in periods of illumination, although not under darkened conditions. The behavioral abnormalities except vocalization were ameliorated by 10-day oral treatment with risperidone at 0.10 mg/kg/day. Although this study needs to be replicated, this case report suggests the possibility that hyper EGF signals at the perinatal stage of non-human primates result in post-pubertal behavioral/cognitive deficits, which possibly imitate some pathological features of human schizophrenia.

We sought to establish the relationship between fasting plasma glucose concentrations and pancreatic fractional beta cell area in adult cynomolgus monkeys (Macaca fascicularis). Fasting plasma glucose and pancreatic fractional beta cell area were measured in 18 control and 17 streptozotocin-treated adult primates (17.0 ± 1.2 vs 15.4 ± 1.2 years old). Fasting plasma glucose was increased (12.0 ± 2.0 vs 3.4 ± 0.1 mmol/l, p < 0.01) and fractional beta cell area was decreased (0.62 ± 0.13% vs 2.49 ± 0.35%, p < 0.01) in streptozotocin-treated monkeys. The relationship between fasting plasma glucose and pancreatic fractional beta cell area was described by a wide range of beta cell areas in controls. In streptozotocin-treated monkeys there was an inflection of fasting blood glucose at ∼50% of the mean beta cell area in controls with a steep increase in blood glucose for each further decrement in beta cell area. In adult non-human primates a decrement in fractional beta cell area of ∼50% or more leads to loss of glycaemic control.

Inhibition of plasminogen activator inhibitor (PAI)-1 is useful to treat several disorders including thrombosis. An inhibitor of PAI-1 (TM5275) was newly identified by an extensive study of structure-activity relationship based on a lead compound (TM5007) which was obtained through virtual screening by docking simulations. Its antithrombotic efficacy and adverse effects were tested in vivo in rats and nonhuman primates (cynomolgus monkey). TM5275, administered orally in rats (1 to 10 mg/kg), has an antithrombotic effect equivalent to that of ticlopidine (500 mg/kg) in an arterialvenous shunt thrombosis model and to that of clopidogrel (3 mg/kg) in a ferric chloride-treated carotid artery thrombosis model. TM5275 does not modify activated partial thromboplastin time and prothrombin time or platelet activity and does not prolong bleeding time. Combined with tissue plasminogen activator, TM5275 improves the latter's therapeutic efficacy and reduces its adverse effect. Administered to a monkey model of photochemical induced arterial thrombosis, TM5275 (10 mg/kg) has the same antithrombotic effect as clopidogrel (10 mg/kg), without enhanced bleeding. This study documents the antithrombotic benefits of a novel, more powerful, PAI-1 inhibitor in rats and, for the first time, in nonhuman primates. These effects are obtained without adverse effect on bleeding time. Journal of Cerebral Blood Flow & Metabolism (2010) 30, 904-912; doi: 10.1038/jcbfm.2009.272; published online 20 January 2010

We sought to establish the relationship between fasting plasma glucose concentrations and pancreatic fractional beta cell area in adult cynomolgus monkeys (Macaca fascicularis). Fasting plasma glucose and pancreatic fractional beta cell area were measured in 18 control and 17 streptozotocin-treated adult primates (17.0 ± 1.2 vs 15.4 ± 1.2 years old). Fasting plasma glucose was increased (12.0 ± 2.0 vs 3.4 ± 0.1 mmol/l, p < 0.01) and fractional beta cell area was decreased (0.62 ± 0.13% vs 2.49 ± 0.35%, p < 0.01) in streptozotocin-treated monkeys. The relationship between fasting plasma glucose and pancreatic fractional beta cell area was described by a wide range of beta cell areas in controls. In streptozotocin-treated monkeys there was an inflection of fasting blood glucose at ∼50% of the mean beta cell area in controls with a steep increase in blood glucose for each further decrement in beta cell area. In adult non-human primates a decrement in fractional beta cell area of ∼50% or more leads to loss of glycaemic control.

Background and methods: Quantitative enzyme-immunoassays of urinary and fecal immunoglobulin A (IgA), cortisol and 11-17-dioxoandrostanes (11,17-DOA), and serum cortisol in eight metabolic-cage-housed female cynomolgus monkeys were performed. The monkeys were divided into two groups, B and NB. Group B animals were blood sampled every 6 hours, whereas Group NB animals were not handled/blood sampled. Results: No differences were recorded between the amounts of feces and urine excreted by the two groups. Group B animals excreted more urinary cortisol than did Group NB animals indicating that restraint-blood sampling resulted in a stress response. Excreted amounts of IgA and 11,17-DOA (urine and feces) did not differ between the groups. Conclusion: Urinary cortisol was a reliable marker of the stress associated with repeated blood sampling. Declining amounts of excreted urinary cortisol indicated that cynomolgus monkeys acclimated quickly to repeated blood sampling in metabolism cages. Within and between animal variation in amounts of feces voided demonstrated the importance of expressing fecal markers as 'amounts excreted per time unit per kg body weight' rather than just measuring the concentrations in fecal samples.