BACE1-cleavage of Sez6 and Sez6L is elevated in Niemann-Pick type C disease mouse brains

It is intriguing that a rare, inherited lysosomal storage disorder Niemann-Pick type C (NPC) shares similarities with Alzheimer’s disease (AD). We have previously reported an enhanced processing of β-amyloid precursor protein (APP) by β-secretase (BACE1), a key enzyme in the pathogenesis of AD, in NPC1-null cells. In this work, we characterized regional and temporal expression and processing of the recently identified BACE1 substrates seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L), and APP, in NPC1-/- (NPC1) and NPC1+/+ (wt) mouse brains. We analysed 4-weeks old brains to detect the earliest changes associated with NPC, and 10-weeks of age to identify changes at terminal disease stage. Sez6 and Sez6L were selected due to their predominant cleavage by BACE1, and their potential role in synaptic function that may contribute to presentation of seizures and/or motor impairments in NPC patients. While an enhanced BACE1-cleavage of all three substrates was detected in NPC1 vs. wt-mouse brains at 4- weeks of age, at 10-weeks increased proteolysis by BACE1 was observed for Sez6L in the cortex, hippocampus and cerebellum of NPC1-mice. Interestingly, both APP and Sez6L were found to be expressed in Purkinje neurons and their immunostaining was lost upon Purkinje cell neurodegeneration in 10-weeks old NPC1 mice. Furthermore, in NPC1- vs. wt-mouse primary cortical neurons, both Sez6 and Sez6L showed increased punctuate staining within the endolysosomal pathway as well as increased Sez6L and BACE1-positive puncta. This indicates that a trafficking defect within the endolysosomal pathway may play a key role in enhanced BACE1-proteolysis in NPC disease. Overall, our findings suggest that enhanced proteolysis by BACE1 could be a part of NPC disease pathogenesis. Understanding the basic biology of BACE1 and the functional impact of cleavage of its substrates is important to better evaluate the therapeutic potential of BACE1 against AD and, possibly, NPC disease

Embodied Emotion Modulates Neural Signature of Performance Monitoring

BACKGROUND:Recent research on the "embodiment of emotion" implies that experiencing an emotion may involve perceptual, somatovisceral, and motor feedback aspects. For example, manipulations of facial expression and posture appear to induce emotional states and influence how affective information is processed. The present study investigates whether performance monitoring, a cognitive process known to be under heavy control of the dopaminergic system, is modulated by induced facial expressions. In particular, we focused on the error-related negativity, an electrophysiological correlate of performance monitoring. METHODS/PRINCIPAL FINDINGS:During a choice reaction task, participants held a Chinese chop stick either horizontally between the teeth ("smile" condition) or, in different runs, vertically ("no smile") with the upper lip. In a third control condition, no chop stick was used ("no stick"). It could be shown on a separate sample that the facial feedback procedure is feasible to induce mild changes in positive affect. In the ERP sample, the smile condition, hypothesized to lead to an increase in dopaminergic activity, was associated with a decrease of ERN amplitude relative to "no smile" and "no stick" conditions. CONCLUSION:Embodying emotions by induced facial expressions leads to a changes in the neural correlates of error detection. We suggest that this is due to the joint influence of the dopaminergic system on positive affect and performance monitoring

Resisting Sleep Pressure:Impact on Resting State Functional Network Connectivity

In today's 24/7 society, sleep restriction is a common phenomenon which leads to increased levels of sleep pressure in daily life. However, the magnitude and extent of impairment of brain functioning due to increased sleep pressure is still not completely understood. Resting state network (RSN) analyses have become increasingly popular because they allow us to investigate brain activity patterns in the absence of a specific task and to identify changes under different levels of vigilance (e.g. due to increased sleep pressure). RSNs are commonly derived from BOLD fMRI signals but studies progressively also employ cerebral blood flow (CBF) signals. To investigate the impact of sleep pressure on RSNs, we examined RSNs of participants under high (19 h awake) and normal (10 h awake) sleep pressure with three imaging modalities (arterial spin labeling, BOLD, pseudo BOLD) while providing confirmation of vigilance states in most conditions. We demonstrated that CBF and pseudo BOLD signals (measured with arterial spin labeling) are suited to derive independent component analysis based RSNs. The spatial map differences of these RSNs were rather small, suggesting a strong biological substrate underlying these networks. Interestingly, increased sleep pressure, namely longer time awake, specifically changed the functional network connectivity (FNC) between RSNs. In summary, all FNCs of the default mode network with any other network or component showed increasing effects as a function of increased 'time awake'. All other FNCs became more anti-correlated with increased 'time awake'. The sensorimotor networks were the only ones who showed a within network change of FNC, namely decreased connectivity as function of 'time awake'. These specific changes of FNC could reflect both compensatory mechanisms aiming to fight sleep as well as a first reduction of consciousness while becoming drowsy. We think that the specific changes observed in functional network connectivity could imply an impairment of information transfer between the affected RSNs

Impact of ApoB-100 expression on cognition and brain pathology in wild-type and hAPPsl mice

During their lifetime, people are commonly exposed to several vascular risk factors that may affect brain ageing and cognitive function. In the last few years, increasing evidence suggests that pathological plasma lipid profiles contribute to the pathogenesis of late-onset Alzheimer's disease. Importantly, hypercholesterolemia, especially elevated low-density lipoprotein cholesterol values, that is, increased apolipoprotein B-100 (ApoB-100) levels, represents an independent risk factor. In this study, the effects of ApoB-100 overexpression, either alone or in combination with cerebral expression of human amyloid precursor protein (hAPP), on cognitive functions and brain pathology were assessed. Our results show that ApoB-100 overexpression induces memory decline and increases cerebral lipid peroxidation and amyloid beta levels compared to those in wild-type animals. Although double-transgenic ApoBxAPP animals did not develop more distinct behavioral deficits than single-transgenic hAPP littermates, hApoB-100 expression caused additional pathophysiological features, such as high LDL and low HDL-cholesterol levels, increased lipid peroxidation, and pronounced ApoB-100 accumulation in cerebral vessels. Thus, our results indicate that ApoBxAPP mice might better reflect the situation of elderly humans than hAPPsl overexpression alone. (C) 2013 Elsevier Inc. All rights reserved

Time course and progression of wild type α-Synuclein accumulation in a transgenic mouse model

Abstract Background Progressive accumulation of α-synuclein (α-Syn) protein in different brain regions is a hallmark of synucleinopathic diseases, such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy. α-Syn transgenic mouse models have been developed to investigate the effects of α-Syn accumulation on behavioral deficits and neuropathology. However, the onset and progression of pathology in α-Syn transgenic mice have not been fully characterized. For this purpose we investigated the time course of behavioral deficits and neuropathology in PDGF-β human wild type α-Syn transgenic mice (D-Line) between 3 and 12 months of age. Results These mice showed progressive impairment of motor coordination of the limbs that resulted in significant differences compared to non-transgenic littermates at 9 and 12 months of age. Biochemical and immunohistological analyses revealed constantly increasing levels of human α-Syn in different brain areas. Human α-Syn was expressed particularly in somata and neurites of a subset of neocortical and limbic system neurons. Most of these neurons showed immunoreactivity for phosphorylated human α-Syn confined to nuclei and perinuclear cytoplasm. Analyses of the phenotype of α-Syn expressing cells revealed strong expression in dopaminergic olfactory bulb neurons, subsets of GABAergic interneurons and glutamatergic principal cells throughout the telencephalon. We also found human α-Syn expression in immature neurons of both the ventricular zone and the rostral migratory stream, but not in the dentate gyrus. Conclusion The present study demonstrates that the PDGF-β α-Syn transgenic mouse model presents with early and progressive accumulation of human α-Syn that is accompanied by motor deficits. This information is essential for the design of therapeutical studies of synucleinopathies.</p