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Highlights • Panel of the largest 97 commercial banks listed in 11 EU countries for the period 2005–2016. • The standard version of leverage ratio is informationally limited for bank's investors. • A three-step bank leverage adjustment is proposed for sterilizing the effect of provisioning and incorporating the effect of credit risk on equity beta coefficient. • Banks' asset quality affects the relationship between leverage and systematic risk. Abstract We analyse how bank asset quality interacts within the relationship between leverage and systematic risk. We elaborate three leverage adjustments for sterilizing the effect of provisioning and incorporating the effect of non-performing loans and total credit risk exposure. We test the model on a sample of 97 European banks from 2005 and 2016. Controlling for size, findings show the relevance of a combined effect of leverage and asset quality as a systematic risk component. NPLs are found to be one significant variable of market risk. Results demonstrate that simple leverage is pointless for verifying the financial riskiness of banks. [ABSTRACT FROM AUTHOR]

To characterize the mechanisms underlying region- and age-dependent hippocampal synaptic dysfunction in Alzheimer's disease, we used transgenic CRND8 mice, expressing the Swedish-Indiana APP mutation. In 2-month-old mice, no β-amyloid plaques deposition, but the presence of soluble oligomers, were found in CA1 area but not in dentate gyrus (DG). At this age, long-term potentiation (LTP) was reduced selectively in CA1. In 6-month-old mice, the presence of soluble oligomers was accompanied by accumulation of β-amyloid plaques and decreased LTP in CA1 and DG regions. In both regions, the loss of LTP was linked to reduced N-methyl-D-aspartate (NMDA) to alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) current ratio. The acetylcholine-esterase inhibitor, neostigmine rescued LTP in CA1 area at early stage of the disease but not after plaques deposition. Conversely, the NMDA receptor antagonist memantine restored LTP selectively in DG at later stages of the disease. Both these effects were associated with a normalization of the NMDA to AMPA ratio. The association between the recovery of LTP and the normalization of the NMDA to AMPA ratio provides information on new possible therapeutic strategies in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Introduction Cell permeable peptides (CPPs) represent a novel tool for the delivery of bioactive molecules into scarcely accessible organs, such as the brain. CPPs have been successfully used in pre-clinical studies for a variety of diseases, ranging from cancer to neurological disorders. However, the mechanisms by which CPPs cross biological membranes, as well as their pharmacokinetic properties, have been poorly explored due to the lack of specific and sensitive analytical methods. Methods In this paper we describe a protocol to quantitatively determine the amount of CPPs in in vitro and in vivo experimental models. To this end we selected the peptide D-JNKI1 that was shown to prevent neurodegeneration in both acute and chronic degenerative disorders. This method allows an accurate quantitative analysis of D-JNKI1 in both neuronal lysates and tissue homogenates using mass spectrometry and stable isotope dilution approach. Results We found that D-JNKI1 crosses cellular membranes with fast kinetics, through an active and passive mechanism. After acute intraperitoneal (ip) administration of D-JNKI1 in mice, the peptide was found in the main organs with particular regard to the liver and kidney. Interestingly, D-JNKI1 crosses the blood brain barrier (BBB) and reaches the brain, where it remains for one week. Discussion The challenge lies in developing the clinical application of therapeutic cell permeable peptides. Discerning pharmacokinetic properties is a high priority to produce a powerful therapeutic strategy. Overall, our data shed light on the pharmacokinetic properties of D-JNKI1 and supports its powerful neuroprotective effect. [ABSTRACT FROM AUTHOR]

Alzheimer disease (AD) is characterized by cognitive impairment that starts with memory loss to end in dementia. Loss of synapses and synaptic dysfunction are closely associated with cognitive impairment in AD patients. Biochemical and pathological evidence suggests that soluble Aβ oligomers correlate with cognitive impairment. Here, we used the TgCRND8 AD mouse model to investigate the role of JNK in long term memory deficits. TgCRND8 mice were chronically treated with the cellpenetrating c-Jun N-terminal kinase inhibitor peptide (D-JNKI1). D-JNKI1, preventing JNK action, completely rescued memory impairments (behavioral studies) as well as the long term potentiation deficits of TgCRND8 mice, Moreover, D-JNKI1 inhibited APP phosphorylation in Thr-668 and reduced the amyloidogenic cleavage of APP and Aβ oligomers in brain parenchyma of treated mice. In conclusion, by regulating key pathogenic mechanisms of AD, JNK might hold promise as innovative therapeutic target. [ABSTRACT FROM AUTHOR]

A hallmark of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide in the brain. Considerable evidence suggests that soluble Aβ oligomers are responsible for the synaptic dysfunction and cognitive deficit observed in AD. However, the mechanism by which these oligomers exert their neurotoxic effect remains unknown. Recently, it was reported that Aβ oligomers bind to the cellular prion protein with high affinity. Here, we show that N1, the main physiological cleavage fragment of the cellular prion protein, is necessary and sufficient for binding early oligomeric intermediates during Aβ polymerization into amyloid fibrils. The ability of N1 to bind Aβ oligomers is influenced by positively charged residues in two sites (positions 23-31 and 95-105) and is dependent on the length of the sequence between them. Importantly, we also show that N1 strongly suppresses Aβ oligomer toxicity in cultured murine hippocampal neurons, in a Caenorhabditis elegans-based assay, and in vivo in a mouse model of Aβ-induced memory dysfunction. These data suggest that N1, or small peptides derived from it, could be potent inhibitors of Aβ oligomer toxicity and represent an entirely new class of therapeutic agents for AD. [ABSTRACT FROM AUTHOR]

Abstract: The c-Jun N-terminal kinase (JNK) is a mitogen-activated protein kinase (MAPK) activated by stress-signals and involved in many different diseases. Previous results proved the powerful effect of the cell permeable peptide inhibitor d-JNKI1 (d-retro-inverso form of c-Jun N-terminal kinase-inhibitor) against neuronal death in CNS diseases, but the precise features of this neuroprotection remain unclear. We here performed cell-free and in vitro experiments for a deeper characterization of d-JNKI1 features in physiological conditions. This peptide works by preventing JNK interaction with its c-Jun N-terminal kinase–binding domain (JBD) dependent targets. We here focused on the two JNK upstream MAPKKs, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 7 (MKK7), because they contain a JBD homology domain. We proved that d-JNKI1 prevents MKK4 and MKK7 activity in cell-free and in vitro experiments: these MAPKK could be considered not only activators but also substrates of JNK. This means that d-JNKI1 can interrupt downstream but also upstream events along the JNK cascade, highlighting a new remarkable feature of this peptide. We also showed the lack of any direct effect of the peptide on p38, MEK1, and extracellular signal-regulated kinase (ERK) in cell free, while in rat primary cortical neurons JNK inhibition activates the MEK1–ERK–Ets1/c-Fos cascade. JNK inhibition induces a compensatory effect and leads to ERK activation via MEK1, resulting in an activation of the survival pathway—(MEK1/ERK) as a consequence of the death pathway—(JNK) inhibition. This study should hold as an important step to clarify the strong neuroprotective effect of d-JNKI1. [Copyright &y& Elsevier]