Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 38543-38554 |
| Number of pages | 12 |
| Journal | Journal of Biological Chemistry |
| Volume | 285 |
| Issue number | 49 |
| DOIs | |
| Publication status | Published - Dec 3 2010 |
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ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
Endocannabinoids prevent β-amyloid-mediated lysosomal destabilization in cultured neurons. / Noonan, Janis; Tanveer, Riffat; Klompas, Allan; Gowran, Aoife; McKiernan, Joanne; Campbell, Veronica A.
In: Journal of Biological Chemistry, Vol. 285, No. 49, 03.12.2010, p. 38543-38554.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Endocannabinoids prevent β-amyloid-mediated lysosomal destabilization in cultured neurons
AU - Noonan, Janis
AU - Tanveer, Riffat
AU - Klompas, Allan
AU - Gowran, Aoife
AU - McKiernan, Joanne
AU - Campbell, Veronica A.
PY - 2010/12/3
Y1 - 2010/12/3
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M110.162040
DO - 10.1074/jbc.M110.162040
M3 - Article
VL - 285
SP - 38543
EP - 38554
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 49
ER -