No abstract

Autophagy is one of the main mechanisms in the pathophysiology of neurodegenerative disease. The accumulation of autophagic vacuoles (AVs) in affected neurons is responsible for amyloid-β (Aβ) production. Previously, we reported that SUMO1 (small ubiquitin-like modifier 1) increases Aβ levels. In this study, we explored the mechanisms underlying this. We investigated whether AV formation is necessary for Aβ production by SUMO1. Overexpression of SUMO1 increased autophagic activation, inducing the formation of LC3-II-positive AVs in neuroglioma H4 cells. Consistently, autophagic activation was decreased by the depletion of SUMO1 with small hairpin RNA (shRNA) in H4 cells. The SUMO1-mediated increase in Aβ was reduced by the autophagy inhibitors (3-methyladenine or wortmannin) or genetic inhibitors (siRNA targeting ATG5, ATG7, ATG12, or HIF1A), respectively. Accumulation of SUMO1, ATG12, and LC3 was seen in amyloid precursor protein transgenic mice. Our results suggest that SUMO1 accelerates the accumulation of AVs and promotes Aβ production, which is a key mechanism for understanding the AV-mediated pathophysiology of Alzheimer disease.

ObjectiveWe investigated the differential effects of the antipsychotic drugs olanzapine and haloperidol on MK-801-induced memory impairment and neurogenesis in mice.MethodsMK-801 (0.1 mg/kg) was administered 20 minutes prior to behavioral testing over 9 days. Beginning on the sixth day of MK-801 treatment, either olanzapine (0.05 mg/kg) or haloperidol (0.05 mg/kg) was administered 40 minutes prior to MK-801 for the final 4 days. Spatial memory performance was measured using a Morris water maze (MWM) test for 9 days (four trials/day). Immunohistochemistry with bromodeoxyuridine (BrdU) was used to identify newborn cells labeled in tissue sections from the dentate gyrus of the hippocampus.ResultsMK-801 administration over 9 days significantly impaired memory performance in the MWM test compared to untreated controls (p<0.05) and these deficits were blocked by treatment with olanzapine (p<0.05) but not haloperidol. The administration of MK-801 also resulted in a decrease in the number of BrdU-labeled cells in the dentate gyrus (28.6%; p<0.01), which was prevented by treatment with olanzapine (p<0.05) but not haloperidol.ConclusionThese results suggest that olanzapine has a protective effect against cognitive impairments induced by MK-801 in mice via the stimulating effects of neurogenesis.

The effects of genetic background on fear trace conditioning were evaluated in relation to phosphorylated levels of cAMP response element-binding protein (CREB) in the hippocampus using two different inbred strains of mice, C57BL/6 and DBA/2. The male mice received a trace fear conditioning protocol and unpaired control groups were included to assess nonassociative effects on test performance. Both C57BL/6 and DBA/2 mice with paired training displayed higher freezing responses during testing than those with unpaired training, respectively. The C57BL/6 mice with paired training also displayed higher freezing responses to the tone-CS during testing than the DBA/2 mice with paired training. Because much evidence implicates the hippocampus as an important neural substrate for trace fear conditioning, the engagement of the hippocampus was examined after testing by measuring levels of CREB and phosphorylated CREB (pCREB). The results revealed that hippocampal CREB levels in both strains of mice were not significantly altered according to the type of training (unpaired vs. paired). However, the hippocampal pCREB levels were significantly higher in the paired training group than the unpaired control group in C57BL/6 mice, but not in DBA/2 mice. These findings indicate that hippocampal pCREB is closely tied to this form of associative conditioning only in C57BL/6 mice and that different neural substrates may support trace conditioning in C57BL/6 and DBA/2 strains.