amyloid-beta-peptides and anandamide

N-stearoyltyrosine (NsTyr) as an anandamide (AEA) analog has close relationships with AEA not only in structure but also in terms of biological actions of endocannabinoids. Since β-amyloid (Aβ)-induced primary neuronal injury involves the activation of the endocannabinoid systems (ECS), the protective effects of NsTyr against Aβ(1-40)-induced neuronal injury and the mechanism were studied systematically in this paper.. Cortical neurons were incubated with Aβ(1-40) for 24 h. NsTyr was added to indicated concentrations 30 min prior to injury.. The best effects of NsTyr on Aβ(1-40)-induced primary neuronal injury occurred at 10 μM. The mechanism of NsTyr on neuroprotective effects against Aβ(1-40)-induced cellular death first involved anti-apoptosis resulting from the activation of cannabinoid receptors, then the pre-receptor regulation of AEA by the inhibition of endocannabinoid inactivation. These data demonstrated that the protective effects of NsTyr on Aβ(1-40)-induced primary neuronal injury resulted from the inhibition of fatty acid amide hydrolase (FAAH) (IC50=16.54 nM) and blocked AEA uptake mediated by anandamide membrane transporter (AMT) (IC50=11.74 nM).. The activation of ECS by inhibiting the degradation of AEA is an effective pharmacological approach to suppress Aβ-induced neuropathic injury. Our research could result in a more realistic alternative for AD treatment.

Topics: Amidohydrolases; Amyloid beta-Peptides; Animals; Apoptosis; Arachidonic Acids; Cerebral Cortex; Dose-Response Relationship, Drug; Endocannabinoids; Inhibitory Concentration 50; Membrane Transport Proteins; Neurons; Neuroprotective Agents; Peptide Fragments; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Tyrosine

Aberrant Notch signaling has recently emerged as a possible mechanism for the altered neurogenesis, cognitive impairment, and learning and memory deficits associated with Alzheimer disease (AD). Recently, targeting the endocannabinoid system in models of AD has emerged as a potential approach to slow the progression of the disease process. Although studies have identified neuroprotective roles for endocannabinoids, there is a paucity of information on modulation of the pro-survival Notch pathway by endocannabinoids. In this study the influence of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol, on the Notch-1 pathway and on its endogenous regulators were investigated in an in vitro model of AD. We report that AEA up-regulates Notch-1 signaling in cultured neurons. We also provide evidence that although Aβ(1-42) increases expression of the endogenous inhibitor of Notch-1, numb (Nb), this can be prevented by AEA and 2-arachidonoylglycerol. Interestingly, AEA up-regulated Nct expression, a component of γ-secretase, and this was found to play a crucial role in the enhanced Notch-1 signaling mediated by AEA. The stimulatory effects of AEA on Notch-1 signaling persisted in the presence of Aβ(1-42). AEA was found to induce a preferential processing of Notch-1 over amyloid precursor protein to generate Aβ(1-40). Aging, a natural process of neurodegeneration, was associated with a reduction in Notch-1 signaling in rat cortex and hippocampus, and this was restored with chronic treatment with URB 597. In summary, AEA has the proclivity to enhance Notch-1 signaling in an in vitro model of AD, which may have relevance for restoring neurogenesis and cognition in AD.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Arachidonic Acids; Benzamides; Carbamates; Cells, Cultured; Cerebral Cortex; Endocannabinoids; Gene Expression Regulation, Enzymologic; Glycerides; Hippocampus; Male; Membrane Glycoproteins; Neurons; Peptide Fragments; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptor, Notch1; Signal Transduction; Up-Regulation

Cannabinoid receptor agonists including anandamide and noladin either have recently been suggested to exhibit neuroprotective properties. The amyloid-beta (Abeta) peptide is thought to be responsible for the neurodegenerative changes associated with Alzheimer's disease pathology. This study characterizes the effects of anandamide and noladin ether on the neurotoxicity of Abeta in differentiated human teratocarcinoma cell line, Ntera 2/cl-D1 neurons. Anandamide and noladin ether, at nanomolar concentrations, showed concentration dependent inhibition of Abeta toxicity. A CB(1) cannabinoid receptor antagonist, AM251, prevented the protective effects of anandamide and noladin ether. The mitogen activated protein kinase (MAPK) pathway inhibitor PD98059 also prevented the protective effects of cannabinoids and corticotrophin-releasing hormone. These results suggest that activation of the MAPK pathway by either cannabinoids or corticotrophin-releasing hormone could be used to prevent Abeta peptide induced neurodegeneration.

Topics: Amyloid beta-Peptides; Arachidonic Acids; Cannabinoids; Corticotropin-Releasing Hormone; Endocannabinoids; Enzyme Inhibitors; Flavonoids; Glycerides; Humans; Mitogen-Activated Protein Kinases; Nervous System Diseases; Neurons; Neuroprotective Agents; Neurotoxins; Oxidation-Reduction; Peptide Fragments; Polyunsaturated Alkamides; Receptors, Cannabinoid; Receptors, Drug