Functional comparison of rod and cone Gα(t) on the regulation of light sensitivity.

The signaling cascades mediated by G protein-coupled receptors (GPCRs) exhibit a wide spectrum of spatial and temporal response properties to fulfill diverse physiological demands. However, the mechanisms that shape the signaling response of the GPCR are not well understood. In this study, we replaced cone transducin α (cTα) for rod transducin α (rTα) in rod photoreceptors of transgenic mice, which also express S opsin, to evaluate the role of Gα subtype on signal amplification from different GPCRs in the same cell; such analysis may explain functional differences between retinal rod and cone photoreceptors.

Using proteomics and network analysis to elucidate the consequences of synaptic protein oxidation in a PS1 + AbetaPP mouse model of Alzheimer's disease.

Increasing evidence suggests that oxidative injury is involved in the pathogenesis of many age-related neurodegenerative disorders, including Alzheimer's disease (AD). Identifying the protein targets of oxidative stress is critical to determine which proteins may be responsible for the neuronal impairments and subsequent cell death that occurs in AD. In this study, we have applied a high-throughput shotgun proteomic approach to identify the targets of protein carbonylation in both aged and PS1 + AbetaPP transgenic mice.

Reduced neuronal expression of synaptic transmission modulator HNK-1/neural cell adhesion molecule as a potential consequence of amyloid beta-mediated oxidative stress: a proteomic approach.

Abstract Oxidative stress imparted by reactive oxygen species (ROS) is implicated in the pathogenesis of Alzheimer's disease (AD). Given that amyloid beta (Abeta) itself generates ROS that can directly damage proteins, elucidating the functional consequences of protein oxidation can enhance our understanding of the process of Abeta-mediated neurodegeneration. In this study, we employed a biocytin hydrazide/streptavidin affinity purification methodology followed by two-dimensional liquid chromatography tandem mass spectrometry coupled with SEQUEST bioinformatics technology, to identify the targets of Abeta-induced oxidative stress in cultured primary cortical mouse neurons.

Rapid characterization of amyloid-beta side-chain oxidation by tandem mass spectrometry and the scoring algorithm for spectral analysis.

Purpose: Amyloid-beta (Abeta) is a self-aggregating protein found in senile plaques in Alzheimer's disease (AD) brain and is thought to play a major role in the disease process. Oxidative stress may be a predominant cause of the formation of these Abeta aggregates. This study aims at identifying possible sites of copper-catalyzed oxidation of Abeta1-40 using liquid chromatography tandem mass spectrometry (LC/MS/MS) and scoring algorithm for spectral analysis (SALSA).

High-throughput proteomic-based identification of oxidatively induced protein carbonylation in mouse brain.

Purpose: The major initiative of this study was to implement a novel proteomic approach in order to detect protein carbonylation in aged mouse brain. Several lines of evidence indicate that reactive oxygen species (ROS)-induced protein oxidation plays an essential role in the initiation of age-related neuropathologies. Therefore, the identification of free radical or peroxide substrates would provide further insight into key biochemical mechanisms that contribute to the progression of certain neurological disorders.

Aberrant sphingomyelin/ceramide metabolic-induced neuronal endosomal/lysosomal dysfunction: potential pathological consequences in age-related neurodegeneration.

Alterations in the trafficking and function of the endocytic pathway have been extensively documented to be one of the earliest pathological changes in sporadic Alzheimer's disease (AD). Although the pathophysiological consequences of these endosomal/lysosomal changes are currently unknown, several recent studies have suggested that such changes in endocytic function are able to cause a redistribution of several lysosomal hydrolases into early endosomes, leading to the overproduction of neurotoxic amyloid peptide. Recently, we and others have demonstrated that abnormal endocytic pathology within post-mitotic neurons can, in part, be attributed to alterations in sphingomyelin/ceramide metabolism, resulting in the intracellular accumulation of ceramide.

Neuronal endosomal/lysosomal membrane destabilization activates caspases and induces abnormal accumulation of the lipid secondary messenger ceramide.

Impairment of endosomal/lysosomal functions are reported as some of the earliest changes in several age-related neurological disorders such as Alzheimer's disease. Dysregulation of the lysosomal system is also accompanied by the accumulation of age-associated pigments and several recent reports have indicated that this age-related lipofuscin accumulation can sensitize cells to oxidative stress and apoptotic cell death. In this study, we have established and evaluated an in vitro age-related pathology paradigm that models lipofuscin accumulation.

The influence of the carboxyl terminus of the Alzheimer Abeta peptide on its conformation, aggregation, and neurotoxic properties.

The amyloid beta-peptide (Abeta) is a 39-43 residue amphipathic peptide that is the major proteinaceous component of senile plaques that are characteristic of Alzheimer's disease (AD). To examine the contribution of the hydrophobic carboxyl-terminal domain on the aggregation, fibril formation, and neurotoxic activity, we have examined the effect of substituting the carboxyl-terminal residues 29-42 derived from two other type I transmembrane proteins: the beta-adrenergic and low-density lipoprotein (LDL) receptor. The chimeric peptides, Abeta1-28ADR29-42 and Abeta1-28LDL29-42, have the same high beta-sheet content as human Abeta1-42 in solution at pH 7.

Prostaglandin E2 transactivates EGF receptor: a novel mechanism for promoting colon cancer growth and gastrointestinal hypertrophy.

Prostaglandins (PGs), bioactive lipid molecules produced by cyclooxygenase enzymes (COX-1 and COX-2), have diverse biological activities, including growth-promoting actions on gastrointestinal mucosa. They are also implicated in the growth of colonic polyps and cancers. However, the precise mechanisms of these trophic actions of PGs remain unclear.