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An amyloid β42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer's disease.

Abstract

The endocannabinoids and their attending cannabinoid (CB)(1) receptors have been implicated in the control of cognition, but their possible roles in dementias are still unclear. In the present study, we used liquid chromatography/mass spectrometry to conduct an endocannabinoid-targeted lipidomic analysis of postmortem brain samples from 38 Alzheimer's disease (AD) patients and 17 control subjects, matched for age and postmortem interval. The analysis revealed that midfrontal and temporal cortex tissue from AD patients contains, relative to control subjects, significantly lower levels of the endocannabinoid anandamide and its precursor 1-stearoyl, 2-docosahexaenoyl-sn-glycero-phosphoethanolamine-N-arachidonoyl (NArPE). No such difference was observed with the endocannabinoid 2-arachidonoyl-sn-glycerol or 15 additional lipid species. In AD patients, but not in control subjects, statistically detectable positive correlations were found between (1) anandamide content in midfrontal cortex and scores of the Kendrick's Digit Copy test (p = 0.004, r = 0.81; n = 10), which measures speed of information processing; and (2) anandamide content in temporal cortex and scores of the Boston Naming test (p = 0.027, r = 0.52; n = 18), which assesses language facility. Furthermore, anandamide and NArPE levels in midfrontal cortex of the study subjects inversely correlated with levels of the neurotoxic amyloid peptide, amyloid β-protein (Aβ)(42), while showing no association with Aβ(40) levels, amyloid plaque load or tau protein phosphorylation. Finally, high endogenous levels of Aβ(42) in Swedish mutant form of amyloid precursor protein (APP(SWE))/Neuro-2a cells directly reduced anandamide and NArPE concentrations in cells lysates. The results suggest that an Aβ(42)-dependent impairment in brain anandamide mobilization contributes to cognitive dysfunction in AD.

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  • Authors+Show Affiliations

    ,

    Department of Pharmacology, University of California, Irvine, Irvine, CA 92697-4625, USA.

    , , , , , ,

    Source

    Neurobiology of aging 33:8 2012 Aug pg 1522-32

    MeSH

    Aged
    Alzheimer Disease
    Amyloid beta-Peptides
    Arachidonic Acids
    Cadaver
    Cerebral Cortex
    Cognition Disorders
    Endocannabinoids
    Female
    Humans
    Lipid Metabolism
    Male
    Peptide Fragments
    Polyunsaturated Alkamides
    Tissue Distribution

    Pub Type(s)

    Journal Article
    Research Support, American Recovery and Reinvestment Act
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21546126

    Citation

    TY - JOUR T1 - An amyloid β42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer's disease. AU - Jung,Kwang-Mook, AU - Astarita,Giuseppe, AU - Yasar,Sevil, AU - Vasilevko,Vitaly, AU - Cribbs,David H, AU - Head,Elizabeth, AU - Cotman,Carl W, AU - Piomelli,Daniele, Y1 - 2011/05/04/ PY - 2010/9/28/received PY - 2010/12/14/revised PY - 2011/3/15/accepted PY - 2011/5/4/aheadofprint PY - 2011/5/7/entrez PY - 2011/5/7/pubmed PY - 2012/10/25/medline SP - 1522 EP - 32 JF - Neurobiology of aging JO - Neurobiol. Aging VL - 33 IS - 8 N2 - The endocannabinoids and their attending cannabinoid (CB)(1) receptors have been implicated in the control of cognition, but their possible roles in dementias are still unclear. In the present study, we used liquid chromatography/mass spectrometry to conduct an endocannabinoid-targeted lipidomic analysis of postmortem brain samples from 38 Alzheimer's disease (AD) patients and 17 control subjects, matched for age and postmortem interval. The analysis revealed that midfrontal and temporal cortex tissue from AD patients contains, relative to control subjects, significantly lower levels of the endocannabinoid anandamide and its precursor 1-stearoyl, 2-docosahexaenoyl-sn-glycero-phosphoethanolamine-N-arachidonoyl (NArPE). No such difference was observed with the endocannabinoid 2-arachidonoyl-sn-glycerol or 15 additional lipid species. In AD patients, but not in control subjects, statistically detectable positive correlations were found between (1) anandamide content in midfrontal cortex and scores of the Kendrick's Digit Copy test (p = 0.004, r = 0.81; n = 10), which measures speed of information processing; and (2) anandamide content in temporal cortex and scores of the Boston Naming test (p = 0.027, r = 0.52; n = 18), which assesses language facility. Furthermore, anandamide and NArPE levels in midfrontal cortex of the study subjects inversely correlated with levels of the neurotoxic amyloid peptide, amyloid β-protein (Aβ)(42), while showing no association with Aβ(40) levels, amyloid plaque load or tau protein phosphorylation. Finally, high endogenous levels of Aβ(42) in Swedish mutant form of amyloid precursor protein (APP(SWE))/Neuro-2a cells directly reduced anandamide and NArPE concentrations in cells lysates. The results suggest that an Aβ(42)-dependent impairment in brain anandamide mobilization contributes to cognitive dysfunction in AD. SN - 1558-1497 UR - https://www.unboundmedicine.com/medline/citation/21546126/abstract/An_amyloid_β_42__dependent_deficit_in_anandamide_mobilization_is_associated_with_cognitive_dysfunction_in_Alzheimer's_disease_ L2 - http://linkinghub.elsevier.com/retrieve/pii/S0197-4580(11)00084-4 ER -