Intracellular signaling lipids control a large variety of cellular processes, including membrane trafficking, cytoskeletal dynamics, transport across membranes and signal transduction. Not surprisingly, lipid signaling and alterations thereof are increasingly linked to human disease. Alzheimer's disease (AD) is one such disorder in which lipid dyshomeostasis and membrane trafficking defects are believed to play a critical role. This concept is easily reconciled with the fact that the main molecular players in AD, including amyloid precursor protein (APP) and the ?-, ?- and ?-secretases, are all transmembrane proteins (or protein complexes) that traffic in cells and exert their functions at or within cellulr membranes. Our working hypothesis is that specific lipid changes may drive or mediate fundamental aspects of AD pathogenesis. Systems-based approaches, such as """"""""lipidomics"""""""", are emerging as a powerful tool to profile cells, tissues or organisms in a diseased state, providing both an unbiased and comprehensive picture of lipid alterations potentially linked to pathogenicity. To better understand the link between lipid signaling defects and AD pathogenesis, we have recently conducted a lipidomic analysis of brain samples derived from three transgenic animal models of familial AD as well as three independent brain regions from patients with late-onset AD. We found that out of 330 lipid species analyzed, only one lipid species was significantly reduced in AD-affected brain regions in mice (forebrain) and men (entorhinal and prefrontal cortex): phosphatidylinositol-3-phosphate (PI3P). PI3P is a phosphoinositide primarily synthesized by lipid kinase Vps34 and acts as a master regulator of the endosomal and autophagy pathways. PI3P controls the recruitment of a variety of compartment-specific effectors harboring PI3P binding modules, such as FYVE or PX domains. We found that knocking down/out Vps34 recapitulates salient features linked to AD pathogenesis, namely (i) enlarged endosomes;(ii) aberrant endosomal trafficking and processing of the amyloid precursor protein (APP);and (iii) accumulation of autophagy substrates. Additionally, work from others shows that chronic lack of Vps34 in neurons produces neurodegeneration. Altogether, our results have identified PI3P deficiency as a key factor in AD pathogenesis. This proposal focuses on addressing the consequences of disrupting PI3P signaling on two processes that emerge as critical in AD pathogenesis, namely the endosomal trafficking and processing of APP (Aim 1) and neuronal autophagy (Aim 2). It will also assess the impact of PI3P deficiency on the A? and Tau pathologies in vivo (Aim 3). We anticipate that our studies will provide key insights into the biology of APP and Tau as well as a better understanding of the role of lipid dysregulation in AD pathogenesis.

Public Health Relevance

Lipid dysregulation is believed to play an important role in the pathogenesis of Alzheimer's disease (AD). Our lipidomic analyses of brain tissue derived from mouse models of AD and AD-affected individuals have identified phosphatidylinositol-3-phosphate (PI3P) deficiency as a candidate lipid alteration involved in AD pathogenesis. The goal of the proposed studies is to test the role of PI3P and a key enzyme mediating its synthesis, Vps34, in the traffic of amyloid precursor protein and the clearance of tau aggregates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056049-08
Application #
8695496
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Corriveau, Roderick A
Project Start
2006-07-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Miranda, André M; Lasiecka, Zofia M; Xu, Yimeng et al. (2018) Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures. Nat Commun 9:291
Bravo, Francisca Vaz; Da Silva, Jorge; Chan, Robin Barry et al. (2018) Phospholipase D functional ablation has a protective effect in an Alzheimer's disease Caenorhabditis elegans model. Sci Rep 8:3540
Pera, Marta; Larrea, Delfina; Guardia-Laguarta, Cristina et al. (2017) Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J 36:3356-3371
Wang, Ziqing; Zhang, Feng; He, Jingquan et al. (2017) Binding of PLD2-Generated Phosphatidic Acid to KIF5B Promotes MT1-MMP Surface Trafficking and Lung Metastasis of Mouse Breast Cancer Cells. Dev Cell 43:186-197.e7
Shen, Yihui; Zhao, Zhilun; Zhang, Luyuan et al. (2017) Metabolic activity induces membrane phase separation in endoplasmic reticulum. Proc Natl Acad Sci U S A 114:13394-13399
Williamson, Rebecca L; Laulagnier, Karine; Miranda, André M et al. (2017) Disruption of amyloid precursor protein ubiquitination selectively increases amyloid ? (A?) 40 levels via presenilin 2-mediated cleavage. J Biol Chem 292:19873-19889
Holland, Petter; Knævelsrud, Helene; Søreng, Kristiane et al. (2016) HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels. Nat Commun 7:13889
Hur, Jang Ho; Park, Shi-Young; Dall'Armi, Claudia et al. (2016) Phospholipase D1 deficiency in mice causes nonalcoholic fatty liver disease via an autophagy defect. Sci Rep 6:39170
Marquer, Catherine; Tian, Huasong; Yi, Julie et al. (2016) Arf6 controls retromer traffic and intracellular cholesterol distribution via a phosphoinositide-based mechanism. Nat Commun 7:11919
Oliveira, T G; Chan, R B; Bravo, F V et al. (2016) The impact of chronic stress on the rat brain lipidome. Mol Psychiatry 21:80-8

Showing the most recent 10 out of 44 publications