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Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons*

Open AccessPublished:October 05, 2010DOI:https://doi.org/10.1074/jbc.M110.162040
      Neuronal cell loss underlies the pathological decline in cognition and memory associated with Alzheimer disease (AD). Recently, targeting the endocannabinoid system in AD has emerged as a promising new approach to treatment. Studies have identified neuroprotective roles for endocannabinoids against key pathological events in the AD brain, including cell death by apoptosis. Elucidation of the apoptotic pathway evoked by β-amyloid (Aβ) is thus important for the development of therapeutic strategies that can thwart Aβ toxicity and preserve cell viability. We have previously reported that lysosomal membrane permeabilization plays a distinct role in the apoptotic pathway initiated by Aβ. In the present study, we provide evidence that the endocannabinoid system can stabilize lysosomes against Aβ-induced permeabilization and in turn sustain cell survival. We report that endocannabinoids stabilize lysosomes by preventing the Aβ-induced up-regulation of the tumor suppressor protein, p53, and its interaction with the lysosomal membrane. We also provide evidence that intracellular cannabinoid type 1 receptors play a role in stabilizing lysosomes against Aβ toxicity and thus highlight the functionality of these receptors. Given the deleterious effect of lysosomal membrane permeabilization on cell viability, stabilization of lysosomes with endocannabinoids may represent a novel mechanism by which these lipid modulators confer neuroprotection.

      Introduction

      Alzheimer disease (AD)
      The abbreviations used are: AD
      Alzheimer disease
      β-amyloid
      AEA
      anandamide
      2-AG
      2-arachidonoylglycerol
      CB
      cannabinoid
      LMP
      lysosomal membrane permeabilization
      AO
      acridine orange
      Z-
      benzyloxycarbonyl-
      FMK
      fluoromethyl ketone
      Suc-
      succinimidyl
      ANOVA
      analysis of variance
      RFU
      relative fluorescence unit(s)
      p-p53Ser-15
      p53 phosphorylated on Ser-15
      p-ERKTyr-205
      ERK phosphorylated on Tyr-205.
      is a debilitating illness of the brain defined by the progressive deterioration of cognition and memory as a result of selective neuronal loss in the hippocampus and surrounding areas of the cerebral cortex (
      • Jakob-Roetne R.
      • Jacobsen H.
      ). There is substantial evidence to suggest that at least a subset of neurons in the AD brain die by apoptosis (
      • Ribe E.M.
      • Serrano-Saiz E.
      • Akpan N.
      • Troy C.M.
      ). The principal neuropathological hallmark of the disease, β-amyloid peptide (Aβ), has been shown to induce apoptosis in neuronal cells in vivo and in vitro (
      • Loo D.T.
      • Copani A.
      • Pike C.J.
      • Whittemore E.R.
      • Walencewicz A.J.
      • Cotman C.W.
      ,
      • Yuan J.
      • Yankner B.A.
      ) through a variety of enzymatic pathways that include activation of caspase-3 (
      • Mattson M.P.
      ), calpain (
      • Boland B.
      • Campbell V.
      ,
      • Raynaud F.
      • Marcilhac A.
      ), and lysosomal cathepsins (
      • Boland B.
      • Campbell V.
      ,
      • Fogarty M.P.
      • McCormack R.M.
      • Noonan J.
      • Murphy D.
      • Gowran A.
      • Campbell V.A.
      ).
      Recently, the lysosomal system has been implicated in AD pathogenesis (
      • Fogarty M.P.
      • McCormack R.M.
      • Noonan J.
      • Murphy D.
      • Gowran A.
      • Campbell V.A.
      ,
      • Nixon R.A.
      • Cataldo A.M.
      • Mathews P.M.
      ). Neurons of AD patients demonstrate alterations in the lysosomal system, including the cellular pathways that converge on it, namely endocytosis and autophagy (
      • Nixon R.A.
      • Cataldo A.M.
      • Mathews P.M.
      ,
      • Zheng L.
      • Roberg K.
      • Jerhammar F.
      • Marcusson J.
      • Terman A.
      ). Such alterations include an increase in the size and number of endosomes (
      • Nixon R.A.
      • Cataldo A.M.
      • Mathews P.M.
      ,
      • Bucci C.
      • Parton R.G.
      • Mather I.H.
      • Stunnenberg H.
      • Simons K.
      • Hoflack B.
      • Zerial M.
      ), autophagosomes (
      • Yu W.H.
      • Cuervo A.M.
      • Kumar A.
      • Peterhoff C.M.
      • Schmidt S.D.
      • Lee J.H.
      • Mohan P.S.
      • Mercken M.
      • Farmery M.R.
      • Tjernberg L.O.
      • Jiang Y.
      • Duff K.
      • Uchiyama Y.
      • Näslund J.
      • Mathews P.M.
      • Cataldo A.M.
      • Nixon R.A.
      ) and lysosomes (
      • Nixon R.A.
      • Cataldo A.M.
      • Mathews P.M.
      ) and an increase in the gene expression and synthesis of all classes of lysosomal hydrolases, including cathepsins (
      • Cataldo A.M.
      • Barnett J.L.
      • Berman S.A.
      • Li J.
      • Quarless S.
      • Bursztajn S.
      • Lippa C.
      • Nixon R.A.
      ). In addition to their role in the digestion of cellular waste, it has become clear that partial and selective lysosomal membrane permeabilization (LMP), followed by the release of lysosomal enzymes into the cytosol, can induce apoptotic cell death (
      • Kroemer G.
      • Jäättelä M.
      ). Cathepsins D and L are among the lysosomal proteases that have been implicated in apoptosis by virtue of their ability to activate apoptotic effectors, such as mitochondrial uncoupling and caspases (
      • Boya P.
      • Kroemer G.
      ).
      Among the agents that are capable of destabilizing lysosomes, Aβ has emerged as an inducer of LMP (
      • Yang A.J.
      • Chandswangbhuvana D.
      • Margol L.
      • Glabe C.G.
      ). Cultured primary neurons are able to internalize Aβ from the culture medium where it accumulates within lysosomes, resulting in the loss of lysosomal membrane integrity and activation of the apoptotic cascade (
      • Ditaranto K.
      • Tekirian T.L.
      • Yang A.J.
      ). We have recently identified that Aβ destabilizes lysosomes early in the apoptotic cascade in a manner involving the tumor suppressor protein, p53, and its transcription target, Bax (
      • Fogarty M.P.
      • McCormack R.M.
      • Noonan J.
      • Murphy D.
      • Gowran A.
      • Campbell V.A.
      ). However, the precise mechanism by which Aβ causes lysosomes to become vulnerable to LMP has not yet been resolved.
      The endocannabinoid system has emerged as a promising new target for neuroprotective therapy in AD (
      • Campbell V.A.
      • Gowran A.
      ). This system comprises the G protein-coupled cannabinoid (CB) receptors, CB1 and CB2, their endogenous ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their degradative enzymes (
      • Mackie K.
      • Stella N.
      ). Among their numerous functions, endocannabinoids are believed to play a role in the cell death/survival decision and thus govern cell fate (
      • Guzmán M.
      • Sánchez C.
      • Galve-Roperh I.
      ). Numerous studies have identified neuroprotective roles of the endocannabinoid system against excitotoxicity (
      • Marsicano G.
      • Goodenough S.
      • Monory K.
      • Hermann H.
      • Eder M.
      • Cannich A.
      • Azad S.C.
      • Cascio M.G.
      • Gutiérrez S.O.
      • van der Stelt M.
      • López-Rodriguez M.L.
      • Casanova E.
      • Schütz G.
      • Zieglgänsberger W.
      • Di Marzo V.
      • Behl C.
      • Lutz B.
      ), oxidative stress (
      • Iuvone T.
      • Esposito G.
      • Esposito R.
      • Santamaria R.
      • Di Rosa M.
      • Izzo A.A.
      ), and inflammation (
      • Ehrhart J.
      • Obregon D.
      • Mori T.
      • Hou H.
      • Sun N.
      • Bai Y.
      • Klein T.
      • Fernandez F.
      • Tan J.
      • Shytle R.D.
      ), all key pathological events in the AD brain. Moreover, endocannabinoids have been directly implicated in the protection of neurons against Aβ toxicity (
      • Milton N.G.
      ,
      • van der Stelt M.
      • Mazzola C.
      • Esposito G.
      • Matias I.
      • Petrosino S.
      • De Filippis D.
      • Micale V.
      • Steardo L.
      • Drago F.
      • Iuvone T.
      • Di Marzo V.
      ). Recently, it was reported that CB1 receptors can be targeted to lysosomes via the adaptor protein, AP3, and are capable of mediating signal transduction while located at the lysosomal compartment (
      • Rozenfeld R.
      • Devi L.A.
      ). This spatial compartmentalization suggests a mechanism for diversity in CB1 receptor signaling and indicates a functional role for CB1 receptors at the lysosome. This has prompted us to investigate herein whether the neuroprotective capacity of the endocannabinoid system is based on its ability to stabilize lysosomes and thus block the lysosomal branch of the apoptotic pathway.
      The results from this study indicate that endocannabinoids have the ability to stabilize lysosomes against Aβ-induced LMP and thus may represent a novel target for therapeutic intervention in AD.

      Acknowledgments

      We acknowledge the assistance of Dr. J. F. X. Jones with BODIPY FL-pepstatin A analysis and Dr. A. J. Irving in providing comments on the manuscript.

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