Two substrates of insulin-degrading enzyme (IDE), amyloid ␤-protein (A␤) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of A␤ levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases A␤ and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE ؊͞؊). IDE deficiency resulted in a >50% decrease in A␤ degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE ؊͞؊ mice showed increased cerebral accumulation of endogenous A␤, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the ␤-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD. I nsulin-degrading enzyme (IDE, insulysin) is an Ϸ110-kDa thiol zinc-metalloendopeptidase located in cytosol, peroxisomes, endosomes, and on the cell surface (1-4) that cleaves small proteins of diverse sequence, many of which share a propensity to form ␤-pleated sheet-rich amyloid fibrils under certain conditions [e.g., amyloid ␤-protein (A␤), insulin, glucagon, amylin, atrial natriuretic factor, and calcitonin] (5, 6). IDE is the major enzyme responsible for insulin degradation in vitro (1), but the extent to which it mediates insulin catabolism in vivo has been controversial, with doubts expressed that IDE has any physiological role in insulin catabolism (7). Insulin, which is critical for glucose, lipid, and protein metabolism, as well as for cell growth and differentiation, is cleared mainly by the liver and kidney, but most other tissues also degrade the hormone. It was recently shown that transferring an Ϸ3.7-cM chromosomal region containing the IDE gene from an inbred rat model of type 2 diabetes mellitus (DM2) (the GK rat) to a normoglycemic rat recapitulated several features of the diabetic phenotype, including hyperinsulinemia and postprandial hyperglycemia (8). The GK allele of IDE in this chromosomal region was found to bear two missense mutations that, when transfected into COS-1 cells, resulted in 31% less insulin degradation compared with cells transfected with the WT allele. Furthermore, the IDE region of chromosome 10q has been genetically linked to DM2 (9, 10) and to elevated fasting glucose levels [20-year means (1...

Targeted deletion of two members of the FE65 family of adaptor proteins, FE65 and FE65L1, results in cortical dysplasia. Heterotopias resembling those found in cobblestone lissencephalies in which neuroepithelial cells migrate into superficial layers of the developing cortex, aberrant cortical projections and loss of infrapyramidal mossy fibers arise in FE65/FE65L1 compound null animals, but not in single gene knockouts. The disruption of pial basal membranes underlying the heterotopias and poor organization of fibrillar laminin by isolated meningeal fibroblasts from double knockouts suggests that FE65 proteins are involved in basement membrane assembly. A similar phenotype is observed in triple mutant mice lacking the APP family members APP, APLP1 and APLP2, all of which interact with FE65 proteins, suggesting that this phenotype may be caused by decreased transmission of an APP-dependent signal through the FE65 proteins. The defects observed in the double knockout may also involve the family of Ena/Vasp proteins, which participate in actin cytoskeleton remodeling and interact with the WW domains of FE65 proteins.

Members of the FE65 family of adaptor proteins, FE65, FE65L1, and FE65L2, bind the C-terminal region of the amyloid precursor protein (APP). Overexpression of FE65 and FE65L1 was previously reported to increase the levels of ␣-secretase-derived APP (APPs␣). Increased ␤-amyloid (A␤) generation was also observed in cells showing the FE65-dependent increase in APPs␣. To understand the mechanism for the observed increase in both A␤ and APPs␣ given that ␣-secretase cleavage of a single APP molecule precludes A␤ generation, we examined the effects of FE65L1 overexpression on APP Cterminal fragments (APP CTFs). Our data show that FE65L1 potentiates ␥-secretase processing of APP CTFs, including the amyloidogenic CTF C99, accounting for the ability of FE65L1 to increase generation of APP Cterminal domain and A␤40. The FE65L1 modulation of these processing events requires binding of FE65L1 to APP and APP CTFs and is not because of a direct effect on ␥-secretase activity, because Notch intracellular domain generation is not altered by FE65L1. Furthermore, enhanced APP CTF processing can be detected in early endosome vesicles but not in endoplasmic reticulum or Golgi membranes, suggesting that the effects of FE65L1 occur at or near the plasma membrane. Finally, although FE65L1 increases APP C-terminal domain production, it does not mediate the APP-dependent transcriptional activation observed with FE65.Processing of the amyloid precursor protein (APP) 1 results in the generation of the amyloidogenic peptide, A␤, which plays a central role in the pathogenesis of Alzheimer's disease. Cleavage of C99, the APP C-terminal fragment derived from ␤-secretase processing of APP, by ␥-secretase generates the A␤ peptide. Furthermore, ␥-secretase cleavage of C99 and C83, the ␣-secretase derived APP C-terminal fragment (APP CTF), releases the APP C-terminal domain (AICD), a 6-kDa peptide also called CTF␥ or AID, that regulates transcription after translocation to the nucleus (1-4).The majority of proteins reported to bind the 47-amino acid intracellular region of APP (5-7), including the FE65 protein family members FE65, FE65L1, and FE65L2, bind the YENPTY sorting motif of APP via a phosphotyrosine interaction domain (PID/PTB). YENP is a clathrin-coated pit internalization domain required for trafficking of APP into the endocytic pathway (8, 9). Previous studies have shown that FE65 protein family members can alter the processing of APP by influencing APP trafficking. Increased maturation of APP and increased ␣-secretase-cleaved APP (APPs␣) secretion was observed in H4 neuroglioma cells induced for FE65L1 overexpression (10). Furthermore, enhanced secretion of APPs␣ and A␤ was reported in Madin-Darby canine kidney APP695 cells stably overexpressing FE65 (11). Cell surface APP levels were elevated in these cells, and increased routing of APP into the endocytic pathway from the plasma membrane was suggested to account for the observed increase in A␤ (11).The FE65 proteins are adaptor proteins that have three protein-protein interaction dom...

Although a clinical connection between pain and depression has long been recognized, how these two conditions interact remains unclear. Here we report that both mechanical allodynia and depression-like behavior were significantly exacerbated after peripheral nerve injury in Wistar-Kyoto (WKY) rats, a genetic variation of Wistar rats with demonstrable depression-like behavior. Administration of melatonin into the anterior cingular cortex contralateral to peripheral nerve injury prevented the exacerbation of mechanical allodynia with a concurrent improvement of depressionlike behavior in WKY rats. Moreover, there was a lower plasma melatonin concentration and a lower melatonin receptor expression in the anterior cingular cortex in WKY rats than in Wistar rats. These results suggest that there exists a reciprocal relationship between mechanical allodynia and depression-like behavior and the melotoninergic system in the anterior cingular cortex might play an important role in the interaction between pain and depression.

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Incorporation of bilayer electrodes (Cu:Ag) significantly reduces electrode corrosion and device degradation in perovskite solar cells operating in air. A symbiosis exists whereby Ag inhibits Cu oxidation and Cu prevents interfacial reactions between the perovskite (MAPbI3) and Ag.

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CuInSe 2 (CISe) lattice widens the bandgap from 1.04 eV [5,6] up to 1.68 eV [7] in pure CuGaSe 2 , the change affecting the conduction band and leaving the valence band largely unaffected. [8-10] Since 1994, several studies have focused on optimising device efficiency by adjusting the Ga-concentration profile in the CIGSe layer [3,11,12] nowadays reaching record device efficiencies surpassing 23%. [13] A double Ga-gradient profile (Ga-rich/Ga-poor/Ga-rich) is commonly implemented in high-efficiency CIGSe solar cells. [3,12,14] The gradient in the conduction band assists in driving electrons (minority carriers in p-type CIGSe) towards the space charge region (SCR) and the heterojunction with the n-type CdS layer. [15] The resulting decrease in electron density near the molybdenum (Mo) back contact has been shown to suppress recombination losses, [16-18] notably associated with interfacial recombination at the CIGSe/Mo junction, [14] thereby significantly increasing the device open-circuit voltage (V OC). [19-21] Optimisation of the CIGSe film thickness, composition and Ga-gradient profile has largely been carried out by monitoring improvements in device efficiency, with only limited knowledge of the underlying dynamics and diffusion of the minority carriers to the n-contact. In particular, minority carrier mobility and driftdiffusion times in high-efficiency CIGSe solar cells are important parameters to quantify performance losses in state-of-the-art devices. A number of studies report carrier mobility in CISe and CIGSe measured with a variety of techniques as summarised in Table 1. However, the reported mobility values show variations of several orders of magnitude. Furthermore, only a few studies investigated device-relevant Ga-graded CIGSe layers, instead, focusing on simpler, ungraded absorbers with poorer performance. Combining time-resolved photoluminescence (TRPL) spectroscopy and numerical simulations, Weiss et al. extracted minority carrier mobilities between 32 and 45 cm 2 V −1 s −1 in Gafree CISe absorbers, however for back-graded CIGSe (GGI ratio increasing from 0 to 0.28 towards the back) only a lower limit of 8.3 cm 2 V −1 s −1 could be evidenced. [22] Kuciauskas et al. carried out TRPL studies on a typical Ga gradient device and estimated a minority carrier mobility of 55-230 cm 2 V −1 s −1 in the SCR near the CdS/CIGSe interface, [23] but did not address electron transport across the Ga-gradient towards the back contact region. Though transient absorption spectroscopy (TAS) has been utilized in the fields of organic and hybrid organic-inorganic Cu(In,Ga)Se 2 solar cells have markedly increased their efficiency over the last decades currently reaching a record power conversion efficiency of 23.3%. Key aspects to this efficiency progress are the engineered bandgap gradient profile across the absorber depth, along with controlled incorporation of alkali atoms via post-deposition treatments. Whereas the impact of these treatments on the carrier lifetime has been extensively studied in ungraded Cu(In,Ga...