Lipid alterations in lipid rafts from alzheimer's disease human brain cortex

Lipid rafts are membrane microdomains intimately associated with cell signaling. These biochemical microstructures are characterized by their high contents of sphingolipids, cholesterol and saturated fatty acids and a reduced content of polyunsaturated fatty acids (PUFA). Here, we have purified lipid rafts of human frontal brain cortex from normal and Alzheimer's disease (AD) and characterized their biochemical lipid composition. The results revealed that lipid rafts from AD brains exhibit aberrant lipid profiles compared to healthy brains. In particular, lipid rafts from AD brains displayed abnormally low levels of n-3 long chain polyunsaturated fatty acids (LCPUFA, mainly 22:6n-3, docosahexaenoic acid) and monoenes (mainly 18:1n-9, oleic acid), as well as reduced unsaturation and peroxidability indexes. Also, multiple relationships between phospholipids and fatty acids were altered in AD lipid rafts. Importantly, no changes were observed in the mole percentage of lipid classes and fatty acids in rafts from normal brains throughout the lifespan (24-85 years). These indications point to the existence of homeostatic mechanisms preserving lipid raft status in normal frontal cortex. The disruption of such mechanisms in AD brains leads to a considerable increase in lipid raft order and viscosity, which may explain the alterations in lipid raft signaling observed in AD

Gene expression profile in frontal córtex in sporadic frontotemporal lobar degeneration-TDP

Molecular alterations compromising key metabolic pathways are poorly understood in sporadic frontotemporal lobar degeneration with TDP-43 pathology (sFTLD-TDP). Whole-transcriptome array, RT-qPCR validation, gel electrophoresis, and Western blotting, and mitochondrial electron transport chain (ETC) activity were comparatively examined in frontal cortex (area 8) of 16 sFTLD-TDP cases and 14 controls. Assessment of 111 genes by RT-qPCR showed deregulation of 81 genes linked to neurotransmission and synapses, neuronal architecture, cytoskeleton of axons and dendrites, vesicle trafficking, purines, mitochondria, and energy metabolism in sFTLD-TDP. Western blotting studies disclosed downregulation of several mitochondrial subunits encoded by genomic DNA and MTCO1 encoded by the mitochondrial DNA. Mitochondrial ETC activity of complexes I, IV, and V was decreased in sFTLD-TDP. These findings provide robust information about downregulation of genes involved in vital biochemical pathways and in synaptic neurotransmission which may help to increase understanding about the biochemical substrates of clinical manifestations in sFTLD-TDP. Key Words: Energy metabolism, Frontotemporal lobar degeneration, Mitochondria, Neurotransmission, Purines, Synapses, TDP43

Altered distribution of RhoA in alzheimer's disease and AβPP overexpressing mice

RhoGTPases control cytoskeleton dynamics thereby modulating synaptic plasticity. Because Alzheimer's disease (AD) is characterized by synaptic dysfunction, we sought to determine whether the expression, activity, or localization of the GTPases RhoA, Rac1 and Cdc42, as well as p21-PAK, a downstream target of Rac1/Cdc42, were altered in 18-month-old AbetaPP Tg2576 mice (Swedish mutation) or in brains from patients with AD and, for comparison in the case of RhoA, Pick's disease (PiD), a neurodegenerative disorder characterized by hyper-phosphorylated tau accumulation. Immunohistochemical analyses revealed a distinct localization of each RhoGTPase in synapses, dendrite shafts, neuronal bodies, or astrocytes. The association of RhoA with synapses and dendritic microtubules was confirmed by electron microscopy. In AbetaPP mice, RhoA expression decreased in synapses and increased in dystrophic neurites, suggesting altered subcellular targeting of RhoA. In AD, RhoA immunostaining decreased in the neuropil and markedly increased in neurons, co-localizing with hyperphosphorylated tau inclusions, as though RhoA were sequestered by neurofibrillary tangles. Additionally, total RhoA protein was lower in the AD brain hippocampus, reflecting loss of the membrane bound, presumably active, GTPase. RhoA colocalized with hyperphosphorylated tau in PiD, again suggesting that altered subcellular targeting of RhoA is related to neurodegeneration. No major immunohistochemical changes were observed for Rac1, Cdc42, or p21-PAK, thus identifying RhoA among RhoGTPases as a possible therapeutic target in AD

Transcriptional network analysis in frontal cortex in Lewy body diseases with focus on dementia with Lewy bodies

The present study investigates global transcriptional changes in frontal cortex area 8 in incidental Lewy Body disease (iLBD), Parkinson disease (PD) and Dementia with Lewy bodies (DLB). We identified different co-expressed gene sets associated with disease stages, and gene ontology categories enriched in gene modules and differentially expressed genes including modules or gene clusters correlated to iLBD comprising upregulated dynein genes and taste receptors, and down-regulated innate inflammation. Focusing on DLB, we found modules with genes significantly enriched in functions related to RNA and DNA production, mitochondria and energy metabolism, purine metabolism, chaperone and protein folding system, and synapses and neurotransmission (particularly the GABAergic system). The expression of more than fifty selected genes was assessed with RT-qPCR. Our findings provide, for the first time, evidence of molecular cortical alterations in iLBD and involvement of several key metabolic pathways and gene hubs in DLB which may underlie cognitive impairment and dementia. Key words: Lewy body diseases, dementia with Lewy bodies, cerebral cortex, transcriptome, mitochondria, synapses, neurotransmission, GABA, purine metabolism, chaperones, dynein, axonema, taste receptors

Factors patogènics convergents en taupaties

[cat] En aquesta tesi es presenten un seguit de treballs on s'estudien aspectes patogènics de diferents taupaties tals com l'estrès oxidatiu, la fosforil·lació de la proteína tau, la malfunció de la degradació proteosomal, l'acúmul de factors de transcripció en les inclusions pròpies d'aquestes malalties i el truncatge i degradació de proteïnes.L'objectiu general de la tesi has estat el d'esbrinar els components proteics que, a més de la proteína tau, es troben segrestats en les inclusions de tau en les diferents taupaties. Les diferents taupaties estudiades han estat la malaltia d'Alzheimer, la paràlisi supranuclear progressiva, la malaltia de Pick i la malaltia dels grans argiròfils.La tesi mostra com la majoria de procesos neurodegenratius estudiats són compartits per totes aquestes malalties.[eng] The aim of this thesis has been focused on the study of the common factors that may lead to neuronal degeneration in a bunch of the most frequent tauopathies. We studied oxidative stress, tau phosphorylation and truncation, glia activation, and protein trapping inside tau inclusions.We have seen that most of the neurodegenerative factors studied are quite similar among tauopathies, suggesting a common pathogenic process

Phylogenomic analyses of the genus drosophila reveals genomic signals of climate adaptation

Many Drosophila species differ widely in their distributions and climate niches, making them excellent subjects for evolutionary genomic studies. Here, we have developed a database of high-quality assemblies for 46 Drosophila species and one closely related Zaprionus. Fifteen of the genomes were newly sequenced, and 20 were improved with additional sequencing. New or improved annotations were generated for all 47 species, assisted by new transcriptomes for 19. Phylogenomic analyses of these data resolved several previously ambiguous relationships, especially in the melanogaster species group. However, it also revealed significant phylogenetic incongruence among genes, mainly in the form of incomplete lineage sorting in the subgenus Sophophora but also including asymmetric introgression in the subgenus Drosophila. Using the phylogeny as a framework and taking into account these incongruences, we then screened the data for genome-wide signals of adaptation to different climatic niches. First, phylostratigraphy revealed relatively high rates of recent novel gene gain in three temperate pseudoobscura and five desert-adapted cactophilic mulleri subgroup species. Second, we found differing ratios of nonsynonymous to synonymous substitutions in several hundred orthologues between climate generalists and specialists, with trends for significantly higher ratios for those in tropical and lower ratios for those in temperate-continental specialists respectively than those in the climate generalists. Finally, resequencing natural populations of 13 species revealed tropics-restricted species generally had smaller population sizes, lower genome diversity and more deleterious mutations than the more widespread species. We conclude that adaptation to different climates in the genus Drosophila has been associated with large-scale and multifaceted genomic changes

Transcriptomic taxonomy and neurogenic trajectories of adult human, macaque, and pig hippocampal and entorhinal cells

The hippocampal-entorhinal system supports cognitive functions, has lifelong neurogenic capabilities in many species, and is selectively vulnerable to Alzheimer's disease. To investigate neurogenic potential and cellular diversity, we profiled single-nucleus transcriptomes in five hippocampal-entorhinal subregions in humans, macaques, and pigs. Integrated cross-species analysis revealed robust transcriptomic and histologic signatures of neurogenesis in the adult mouse, pig, and macaque but not humans. Doublecortin (DCX), a widely accepted marker of newly generated granule cells, was detected in diverse human neurons, but it did not define immature neuron populations. To explore species differences in cellular diversity and implications for disease, we characterized subregion-specific, transcriptomically defined cell types and transitional changes from the three-layered archicortex to the six-layered neocortex. Notably, METTL7B defined subregion-specific excitatory neurons and astrocytes in primates, associated with endoplasmic reticulum and lipid droplet proteins, including Alzheimer's disease-related proteins. This resource reveals cell-type- and species-specific properties shaping hippocampal-entorhinal neurogenesis and function

Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex

Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development. Here we identify common variants that alter gene expression (expression quantitative trait loci [eQTLs]) constantly across development or predominantly during prenatal or postnatal stages. Both "constant" and "temporal-predominant" eQTLs are enriched for loci associated with neuropsychiatric traits and disorders and colocalize with specific variants. Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology