Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer's disease (AD). Aβ is generated from sequential cleavages of the β-amyloid precursor protein (APP) by the β-and γ-secretases, and β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase essential for Aβ generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating γ-secretase activity, thereby facilitating Aβ production. There are two highly conserved isoforms of GSK3: GSK3α and GSK3β. We now report that specific inhibition of GSK3β, but not GSK3α, reduced BACE1-mediated cleavage of APP and Aβ production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3β was dependent on NF-κB signaling. Inhibition of GSK3 signaling markedly reduced Aβ deposition and neuritic plaque formation, and rescued memory deficits in the double transgenic AD model mice. These data provide evidence for regulation of BACE1 expression and AD pathogenesis by GSK3β and that inhibition of GSK3 signaling can reduce Aβ neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the β-isoform of GSK3 may be a safe and effective approach for treating AD.

The prevalence of obesity has drastically increased over the last few decades. Exploration into how hunger and satiety signals influence the reward system can help us to understand non-homeostatic mechanisms of feeding. Evidence suggests that insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA remain unknown. We demonstrate that insulin, a circulating catabolic peptide that inhibits feeding, can induce a long-term depression (LTD) of excitatory synapses onto VTA dopamine neurons. This effect requires endocannabinoid-mediated presynaptic inhibition of glutamate release. Furthermore, after a sweetened high fat meal, which elevates endogenous insulin levels, insulin-induced LTD is occluded. Finally, insulin in the VTA reduces food anticipatory behavior and conditioned place preference for food. Taken together, these results suggest that insulin in the VTA suppresses excitatory synaptic transmission and reduces salience of food-related cues.

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J. Neurochem. (2012) 120, 1129–1138. Abstract Deposition of amyloid β protein (Aβ) in the brain is the hallmark of Alzheimer’s disease (AD) pathogenesis. Beta‐site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the β‐secretase in vivo essential for generation of Aβ. Previously we demonstrated that BACE1 is ubiquitinated and the degradation of BACE1 is mediated by the ubiquitin‐proteasome pathway (UPP). However the mechanism underlying regulation of BACE1 degradation by UPP remains elusive. Ubiquitin carboxyl‐terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme highly specific to neuron, catalyzing the hydrolysis of ubiquitin conjugates from ubiquitinated substrates. UCHL1 regulates ubiquitin‐dependent protein degradation. However, whether UCHL1 is particularly involved in the proteasomal degradation of BACE1 and what is the role of UCHL1 in AD pathogenesis remain elusive. To investigate the effect of UCHL1 on BACE1 degradation, HUCH cells, a UCHL1 stably over‐expressed HEK293 cell line, was established. We found that inhibition of UCHL1 significantly increased BACE1 protein level in a time‐dependent manner. Half life of BACE1 was reduced in HUCH cells compared with HEK. Over‐expression of UCHL1 decreased APP C‐terminal fragment C99 and Aβ levels in HUCH cells. Moreover, disruption of Uchl1 gene significantly elevated levels of endogenous BACE1, C99 and Aβ in the Uchl1‐null gad mice. These results demonstrated that UCHL1 accelerates BACE1 degradation and affects APP processing and Aβ production. This study suggests that potentiation of UCHL1 might be able to reduce the level of BACE1 and Aβ in brain, which makes it a novel target for AD drug development.

Soil properties, microbial communities, and enzyme activities were studied in soil planted with transgenic or nontransgenic papaya under field conditions. The transgenic papaya contained a replicase (RP) mutant gene of the papaya ringspot virus (PRSV), which conferred resistance to the virus, the neomycin phosphotransferase II (NPT II) marker gene, which conferred Km resistance, and a cauliflower mosaic virus 35S promoter (CaMV 35S). There were significant differences (P < 0.05) in the total number of colony forming units (CFUs) of bacteria, actinomycetes, and fungi between soils planted with RP-transgenic and nontransgenic plants; total CFUs of bacteria, actinomycetes, and fungi in soil planted with transgenic papaya were significantly higher by 0.43, 0.80, and 0.46 times, respectively. Significantly higher (P < 0.05) CFUs of bacteria, actinomycetes, and fungi resistant to kanamycin (Km) were present in soils planted with the transgenic papaya than in those planted with nontransgenic papaya. Resistance quotients (CFU in the presence of a chemical relative to that without) of Km-resistant bacteria, actinomycetes and fungi were higher in soil planted with transgenic papaya, and the resistance quotients of Km-resistant bacteria, actinomycetes, and fungi in soils planted with transgenic papaya increased statistically significantly (P < 0.05) from 1.5 to 2.5, from 1.2 to 2.6, and from 0.9 to 2.8 times, respectively. Soils planted with transgenic papaya had significantly higher enzyme activities of arylsulfatases (+5.4 times), alkaline phosphatases (+0.5 time), invertase (+0.5 time) and phosphodiesterases (+0.2 time), but lower enzyme activities of proteases (-2.1 times), polyphenol oxidases (-1.4 times), urease (-0.2 time) than the soils planted with nontransgenic papaya. Our results suggest that transgenic papaya could alter chemical properties, enzyme activities, and microbial communities in soil.

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Nanoscale, high surface area cerium oxide (ceria) powders and stable, high-concentration (>1 M) ceria sols were prepared by a new method based on homogeneous precipitation in an acidic environment using cerium(IV) nitrate as the precursor. The results are compared with ceria powders and sols prepared by a hydrothermal method in a basic environment with cerium(III) nitrate as the precursor. Hydrolysis and condensation of the cerium(IV) and cerium(III) nitrates yield the ceria precursor precipitates with molecular formula of CeO 2 ‚2H 2 O [or Ce(OH) 4 ] and CeO 2 ‚H 2 O [or Ce(OH) 2 O], respectively. The dried ceria precursor powders from Ce(IV) and Ce-(III) are well dispersed in the form of primary particles of about 4 nm in size. Calcination at 450 °C causes phase transformation of the amorphous portion accompanying growth of the Ce(IV)derived ceria crystallite or aggregation of the Ce(III)-derived ceria particles. The Ce(III)-derived ceria crystallites have a smaller lattice parameter than the Ce(IV)-derived sample whose lattice parameter decreases with increasing calcination temperature. Stable ceria sols at a solid concentration up to 300 g of CeO 2 /L were obtained from a Ce(IV)-derived ceria precursor powder, as compared to a maximum stable solid concentration of 20 g of CeO 2 /L for the Ce(III)-derived ceria sols. These results are discussed in terms of the shape and aggregation tendency of the primary ceria particles prepared by the two different methods.

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