Anti-apoptotic proteins are oxidized by Aβ25–35 in Alzheimer's fibroblasts

AbstractWe have examined the effects of the beta-amyloid peptide (Aβ25–35) on fibroblasts derived from subjects with Alzheimer's disease (AD) and from age-matched controls. The peptide was significantly more cytotoxic to the AD-derived fibroblasts. The level of protein oxidation was also greater in the cells from AD subjects. Two-dimensional electrophoresis (2-DE) coupled with immunostaining for protein carbonylation revealed specific oxidation-sensitive proteins (OSPs) in both the control and AD-derived cells. Two specific OSPs were identified by mass spectrometry as heat shock protein 60 (HSP 60) and vimentin. Exposure of the cells to Aβ25–35 resulted in a twofold increase in the level of oxidation of these two OSPs in the cells derived from controls, but a ninefold increase in their level of oxidation in the fibroblasts from AD subjects. These observations are of particular interest because of the proposed anti-apoptotic roles of both HSP 60 and vimentin and our recent observation that these same two proteins are particularly susceptible to oxidation in neuronally derived cells

mGluR2/3 activation of the SIRT1 axis preserves mitochondrial function in diabetic neuropathy

ObjectivesThere is a critical need to develop effective treatments for diabetic neuropathy. This study determined if a selective mGluR2/3 receptor agonist prevented or treated experimental diabetic peripheral neuropathy (DPN) through glutamate recycling and improved mitochondrial function.MethodsAdult male streptozotocin treated Spragueâ Dawley rats with features of type 1 diabetes mellitus (T1DM) or Low Capacity Running (LCR) rats with insulin resistance or glucose intolerance were treated with 3 or 10 mg/kg/day LY379268. Neuropathy end points included mechanical allodynia, nerve conduction velocities (NCV), and intraepidermal nerve fiber density (IENFD). Markers of oxidative stress, antioxidant response, glutamate recycling pathways, and mitochondrial oxidative phosphorylation (OXPHOS) associated proteins were measured in dorsal root ganglia (DRG).ResultsIn diabetic rats, NCV and IENFD were decreased. Diabetic rats treated with an mGluR2/3 agonist did not develop neuropathy despite remaining diabetic. Diabetic DRG showed increased levels of oxidized proteins, decreased levels of glutathione, decreased levels of mitochondrial DNA (mtDNA) and OXPHOS proteins. In addition, there was a 20â fold increase in levels of glial fibrillary acidic protein (GFAP) and the levels of glutamine synthetase and glutamate transporter proteins were decreased. When treated with a specific mGluR2/3 agonist, levels of glutathione, GFAP and oxidized proteins were normalized and levels of superoxide dismutase 2 (SOD2), SIRT1, PGCâ 1α, TFAM, glutamate transporter proteins, and glutamine synthetase were increased in DRG neurons.InterpretationActivation of glutamate recycling pathways protects diabetic DRG and this is associated with activation of the SIRT1â PGCâ 1αâ TFAM axis and preservation of mitochondrial OXPHOS function.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/142324/1/acn3484.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/142324/2/acn3484_am.pd

Simultaneous Video Retrieval and Alignment

With the growth of the video streaming industry, video retrieval and video alignment are facing high levels of demand. Several studies have demonstrated the feasibility of these methods for various problems related to video retrieval and alignment independently, but testing in a unified framework has never been done. However, in real-world applications, it is also simultaneously necessary not only to find which video pairs are similar (video retrieval), but also to align the positions of the pairs that are related (video alignment). In this paper, we present a novel task: simultaneous video retrieval and alignment. As a solution to this task, a Simultaneous video Retrieval and Alignment framework, abbreviated as SRA, is proposed, which is a two-stage approach consisting of a foreground proposal stage and a downstream stage to efficiently process untrimmed videos. Furthermore, two criteria are suggested to support the new task: a metric mAP@J assessing how highly related videos are ranked and how well relevant positions are assigned in those videos, and a dataset FIVR+A that includes video-level relationships and hierarchical segment-level annotations. Finally, we conduct multi-pronged analyses to assess how our approach handles the new task in various experiments

Brain diabetic neurodegeneration segregates with low intrinsic aerobic capacity

Objectives Diabetes leads to cognitive impairment and is associated with age‐related neurodegenerative diseases including Alzheimer's disease ( AD ). Thus, understanding diabetes‐induced alterations in brain function is important for developing early interventions for neurodegeneration. Low‐capacity runner ( LCR ) rats are obese and manifest metabolic risk factors resembling human “impaired glucose tolerance” or metabolic syndrome. We examined hippocampal function in aged LCR rats compared to their high‐capacity runner ( HCR ) rat counterparts. Methods Hippocampal function was examined using proton magnetic resonance spectroscopy and imaging, unbiased stereology analysis, and a Y maze. Changes in the mitochondrial respiratory chain function and levels of hyperphosphorylated tau and mitochondrial transcriptional regulators were examined. Results The levels of glutamate, myo ‐inositol, taurine, and choline‐containing compounds were significantly increased in the aged LCR rats. We observed a significant loss of hippocampal neurons and impaired cognitive function in aged LCR rats. Respiratory chain function and activity were significantly decreased in the aged LCR rats. Hyperphosphorylated tau was accumulated within mitochondria and peroxisome proliferator‐activated receptor‐gamma coactivator 1 α , the NAD + ‐dependent protein deacetylase sirtuin 1, and mitochondrial transcription factor A were downregulated in the aged LCR rat hippocampus. Interpretation These data provide evidence of a neurodegenerative process in the hippocampus of aged LCR rats, consistent with those seen in aged‐related dementing illnesses such as AD in humans. The metabolic and mitochondrial abnormalities observed in LCR rat hippocampus are similar to well‐described mechanisms that lead to diabetic neuropathy and may provide an important link between cognitive and metabolic dysfunction.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108300/1/acn386.pd