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.
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.
|McIntire, Laura Beth J; Lee, Kyu-In; Chang-Ileto, Belle et al. (2014) Screening assay for small-molecule inhibitors of synaptojanin 1, a synaptic phosphoinositide phosphatase. J Biomol Screen 19:585-94|
|Wu, Jessica W; Herman, Mathieu; Liu, Li et al. (2013) Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem 288:1856-70|
|Morel, Etienne; Chamoun, Zeina; Lasiecka, Zofia M et al. (2013) Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system. Nat Commun 4:2250|
|Devereaux, Kelly; Dall'Armi, Claudia; Alcazar-Roman, Abel et al. (2013) Regulation of mammalian autophagy by class II and III PI 3-kinases through PI3P synthesis. PLoS One 8:e76405|
|Dall'Armi, Claudia; Devereaux, Kelly A; Di Paolo, Gilbert (2013) The role of lipids in the control of autophagy. Curr Biol 23:R33-45|
|Kang, Min Suk; Baek, Seung-Hoon; Chun, Yoon Sun et al. (2013) Modulation of lipid kinase PI4KII? activity and lipid raft association of presenilin 1 underlies ?-secretase inhibition by ginsenoside (20S)-Rg3. J Biol Chem 288:20868-82|
|Rodriguez-Navarro, Jose Antonio; Kaushik, Susmita; Koga, Hiroshi et al. (2012) Inhibitory effect of dietary lipids on chaperone-mediated autophagy. Proc Natl Acad Sci U S A 109:E705-14|
|Chang-Ileto, Belle; Frere, Samuel G; Di Paolo, Gilbert (2012) Acute manipulation of phosphoinositide levels in cells. Methods Cell Biol 108:187-207|
|Bhalla, Akhil; Vetanovetz, Christopher P; Morel, Etienne et al. (2012) The location and trafficking routes of the neuronal retromer and its role in amyloid precursor protein transport. Neurobiol Dis 47:126-34|
|Di Paolo, Gilbert; Kim, Tae-Wan (2011) Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat Rev Neurosci 12:284-96|
Showing the most recent 10 out of 19 publications