Lipid Rafts and Alzheimer’s Disease: Protein-Lipid Interactions and Perturbation of Signaling

Lipid rafts are membrane domains, more ordered than the bulk membrane and enriched in cholesterol and sphingolipids. They represent a platform for protein-lipid and protein–protein interactions and for cellular signaling events. In addition to their normal functions, including membrane trafficking, ligand binding (including viruses), axonal development and maintenance of synaptic integrity, rafts have also been implicated in the pathogenesis of several neurodegenerative diseases including Alzheimer’s disease (AD). Lipid rafts promote interaction of the amyloid precursor protein (APP) with the secretase (BACE-1) responsible for generation of the amyloid β peptide, Aβ. Rafts also regulate cholinergic signaling as well as acetylcholinesterase and Aβ interaction. In addition, such major lipid raft components as cholesterol and GM1 ganglioside have been directly implicated in pathogenesis of the disease. Perturbation of lipid raft integrity can also affect various signaling pathways leading to cellular death and AD. In this review, we discuss modulation of APP cleavage by lipid rafts and their components, while also looking at more recent findings on the role of lipid rafts in signaling events

The amyloid precursor protein: A biochemical enigma in brain development, function and disease

AbstractFor 20years the amyloid cascade hypothesis of Alzheimer disease (AD) has placed the amyloid-β peptide (Aβ), formed from the amyloid precursor protein (APP), centre stage in the process of neurodegeneration. However, no new therapeutic agents have reached the clinic through exploitation of the hypothesis. The APP metabolites, including Aβ, generated by its proteolytic processing, have distinct physiological functions. In particular, the cleaved intracellular domain of APP (AICD) regulates expression of several genes, including APP itself, the β-secretase BACE-1 and the Aβ-degrading enzyme, neprilysin and this transcriptional regulation involves direct promoter binding of AICD. Of the three major splice isoforms of APP (APP695, APP751, APP770), APP695 is the predominant neuronal form, from which Aβ and transcriptionally-active AICD are preferentially generated by selective processing through the amyloidogenic pathway. Despite intensive research, the normal functions of the APP isoforms remain an enigma. APP plays an important role in brain development, memory and synaptic plasticity and secreted forms of APP are neuroprotective. A fuller understanding of the physiological and pathological actions of APP and its metabolic and gene regulatory network could provide new therapeutic opportunities in neurodegeneration, including AD

Role of Prenatal Hypoxia in Brain Development, Cognitive Functions, and Neurodegeneration

This review focuses on the role of prenatal hypoxia in the development of brain functions in the postnatal period and subsequent increased risk of neurodegenerative disorders in later life. Accumulating evidence suggests that prenatal hypoxia in critical periods of brain formation results in significant changes in development of cognitive functions at various stages of postnatal life which correlate with morphological changes in brain structures involved in learning and memory. Prenatal hypoxia also leads to a decrease in brain adaptive potential and plasticity due to the disturbance in the process of formation of new contacts between cells and propagation of neuronal stimuli, especially in the cortex and hippocampus. On the other hand, prenatal hypoxia has a significant impact on expression and processing of a variety of genes involved in normal brain function and their epigenetic regulation. This results in changes in the patterns of mRNA and protein expression and their post-translational modifications, including protein misfolding and clearance. Among proteins affected by prenatal hypoxia are a key enzyme of the cholinergic system-acetylcholinesterase, and the amyloid precursor protein (APP), both of which have important roles in brain function. Disruption of their expression and metabolism caused by prenatal hypoxia can also result, apart from early cognitive dysfunctions, in development of neurodegeneration in later life. Another group of enzymes affected by prenatal hypoxia are peptidases involved in catabolism of neuropeptides, including amyloid-β peptide (Aβ). The decrease in the activity of neprilysin and other amyloid-degrading enzymes observed after prenatal hypoxia could result over the years in an Aβ clearance deficit and accumulation of its toxic species which cause neuronal cell death and development of neurodegeneration. Applying various approaches to restore expression of neuronal genes disrupted by prenatal hypoxia during postnatal development opens an avenue for therapeutic compensation of cognitive dysfunctions and prevention of Aβ accumulation in the aging brain and the model of prenatal hypoxia in rodents can be used as a reliable tool for assessment of their efficacy

Ontogenetic and Phylogenetic Approaches for Studying the Mechanisms of Cognitive Dysfunctions

This chapter summarizes the phylogenetic and ontogenetic approaches for studying cognitive disorders such as Alzheimer’s disease. It gives an extended example of evaluation of animal behavior and brain properties using an original model of prenatal hypoxia in rats by various physiological, behavioral, immunohistochemical, molecular biological, and biochemical techniques at different stages of postnatal development, which provide a better understanding of the pathological processes in the human brain during the development of neurodegeneration

The Degradome database: mammalian proteases and diseases of proteolysis

The degradome is defined as the complete set of proteases present in an organism. The recent availability of whole genomic sequences from multiple organisms has led us to predict the contents of the degradomes of several mammalian species. To ensure the fidelity of these predictions, our methods have included manual curation of individual sequences and, when necessary, direct cloning and sequencing experiments. The results of these studies in human, chimpanzee, mouse and rat have been incorporated into the Degradome database, which can be accessed through a web interface at http://degradome.uniovi.es. The annotations about each individual protease can be retrieved by browsing catalytic classes and families or by searching specific terms. This web site also provides detailed information about genetic diseases of proteolysis, a growing field of great importance for multiple users. Finally, the user can find additional information about protease structures, protease inhibitors, ancillary domains of proteases and differences between mammalian degradomes

Cortical fast-spiking parvalbumin interneurons enwrapped in the perineuronal net express the metallopeptidases Adamts8, Adamts15 and Neprilysin.

The in situ hybridization Allen Mouse Brain Atlas was mined for proteases expressed in the somatosensory cerebral cortex. Among the 480 genes coding for protease/peptidases, only four were found enriched in cortical interneurons: Reln coding for reelin; Adamts8 and Adamts15 belonging to the class of metzincin proteases involved in reshaping the perineuronal net (PNN) and Mme encoding for Neprilysin, the enzyme degrading amyloid β-peptides. The pattern of expression of metalloproteases (MPs) was analyzed by single-cell reverse transcriptase multiplex PCR after patch clamp and was compared with the expression of 10 canonical interneurons markers and 12 additional genes from the Allen Atlas. Clustering of these genes by K-means algorithm displays five distinct clusters. Among these five clusters, two fast-spiking interneuron clusters expressing the calcium-binding protein Pvalb were identified, one co-expressing Pvalb with Sst (PV-Sst) and another co-expressing Pvalb with three metallopeptidases Adamts8, Adamts15 and Mme (PV-MP). By using Wisteria floribunda agglutinin, a specific marker for PNN, PV-MP interneurons were found surrounded by PNN, whereas the ones expressing Sst, PV-Sst, were not

Chondroitin sulfates and their binding molecules in the central nervous system

Chondroitin sulfate (CS) is the most abundant glycosaminoglycan (GAG) in the central nervous system (CNS) matrix. Its sulfation and epimerization patterns give rise to different forms of CS, which enables it to interact specifically and with a significant affinity with various signalling molecules in the matrix including growth factors, receptors and guidance molecules. These interactions control numerous biological and pathological processes, during development and in adulthood. In this review, we describe the specific interactions of different families of proteins involved in various physiological and cognitive mechanisms with CSs in CNS matrix. A better understanding of these interactions could promote a development of inhibitors to treat neurodegenerative diseases