9 documents found, page 1 of 1
Differential lipid composition and regulation along the hippocampal longitudina...
Miranda, André Miguel; Bravo, Ana Francisca Rodrigues Vaz; Chan, Robin B.; Sousa, Nuno; Di Paolo, Gilbert; Oliveira, Tiago GilLipids are major constituents of the brain largely implicated in physiological and pathological processes. The hippocampus is a complex brain structure involved in learning, memory and emotional responses, and its functioning is also affected in various disorders. Despite conserved intrinsic circuitry, behavioral and anatomical studies suggest the existence of a structural and functional gradient along the hipp...
Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragm...
Miranda, André Miguel Lopes; Lasiecka, Zofia M.; Xu, Yimeng; Neufeld, Jessi; Shahriar, Sanjid; Simoes, Sabrina; Chan, Robin B.; Oliveira, Tiago GilDefects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well ...
Phospholipase D functional ablation has a protective effect in an Alzheimer's d...
Bravo, Francisca Vaz; Da Silva, Jorge; Chan, Robin Barry; Di Paolo, Gilbert; Teixeira-Castro, Andreia; Oliveira, Tiago GilPhospholipase D (PLD) is a key player in the modulation of multiple aspects of cell physiology and has been proposed as a therapeutic target for Alzheimer's disease (AD). Here, we characterize a PLD mutant, pld-1, using the Caenorhabditis elegans animal model. We show that pld-1 animals present decreased phosphatidic acid levels, that PLD is the only source of total PLD activity and that pld-1 animals are more ...
Excess synaptojanin 1 contributes to place cell dysfunction and memory deficits...
Miranda, André Miguel Lopes; Herman, Mathieu; Cheng, Rong; Nahmani, Eden; Barrett, Geoffrey; Micevska, Elizabeta; Fontaine, Gaelle; Potier, Marie-ClaudeThe phosphoinositide phosphatase synaptojanin 1 (SYNJ1) is a key regulator of synaptic function. We first tested whether SYNJ1 contributes to phenotypic variations in familial Alzheimer's disease (FAD) and show that SYNJ1 polymorphisms are associated with age of onset in both early- and late-onset human FAD cohorts. We then interrogated whether SYNJ1 levels could directly affect memory. We show that increased S...
Disruption of amyloid precursor protein ubiquitination selectively increases am...
Williamson, Rebecca L.; Laulagnier, Karine; Miranda, André M.; Fernandez, Marty A.; Wolfe, Michael S.; Sadoul, Rémy; Di Paolo, GilbertAmyloid plaques, a neuropathological hallmark of Alzheimer's disease, are largely composed of amyloid β (Aβ) peptide, derived from cleavage of amyloid precursor protein (APP) by β- and γ-secretases. The endosome is increasingly recognized as an important crossroad for APP and these secretases, with major implications for APP processing and amyloidogenesis. Among various post-translational modifications affectin...
The impact of chronic stress on the rat brain lipidome
Oliveira, Tiago Gil; Chan, Robin B.; Bravo, F. V.; Miranda, A. S.; Silva, R. R.; Zhou, B.; Marques, Fernanda; Pinto, V.; Cerqueira, João JoséChronic stress is a major risk factor for several human disorders that affect modern societies. The brain is a key target of chronic stress. In fact, there is growing evidence indicating that exposure to stress affects learning and memory, decision making and emotional responses, and may even predispose for pathological processes, such as Alzheimer's disease and depression. Lipids are a major constituent of the...
Comparative lipidomic analysis of mouse and human brain with Alzheimer disease
Chan, Robin B.; Oliveira, Tiago Gil; Cortes, Etty P.; Honig, Lawrence S.; Duff, Karen E.; Small, Scott A.; Wenk, Markus R.; Shui, GuanghouLipids are key regulators of brain function and have been increasingly implicated in neurodegenerative disorders including Alzheimer disease (AD). Here, a systems-based approach was employed to determine the lipidome of brain tissues affected by AD. Specifically, we used liquid chromatography-mass spectrometry to profile extracts from the prefrontal cortex, entorhinal cortex, and cerebellum of late-onset AD (LO...
Phospholipase d2 ablation ameliorates Alzheimer's disease-linked synaptic dysfu...
Oliveira, Tiago Gil; Chan, Robin B.; Tian, Huasong; Laredo, Mikael; Shui, Guanghou; Staniszewski, Agnieszka; Zhang, Hong; Wang, Lili; Kim, Tae-WanGrowing evidence implicates aberrant lipid signaling in Alzheimer's disease (AD). While phospholipases A2 and C have been recently shown to mediate key actions of amyloid ß-peptide (Aß) through a dysregulation of arachidonic acid and phosphatidylinositol-4,5-bisphosphate metabolism, respectively, the role of phospholipase D (PLD) has so far remained elusive. PLD produces phosphatidic acid (PA), a bioactive lipi...
Phospholipase D in brain function and Alzheimer's disease
Oliveira, Tiago Gil; Di Paolo, GilbertAlzheimer's disease is the most common neurodegenerative disorder. Although lipids are major constituents of brain, their role in Alzheimer's disease pathogenesis is poorly understood. Much attention has been given to cholesterol, but growing evidence suggests that other lipids, such as phospholipids, might play an important role in this disorder. In this review, we will summarize the evidence linking phospholi...