Title An amyloid β 42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer ' s disease Permalink

The endocannabinoids and their attending CB1 cannabinoid 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 post mortem brain samples from 38 Alzheimer’s disease (AD) patients and 17 control subjects, matched for age and post mortem 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-snglycero-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 (a) anandamide content in midfrontal cortex and scores of the Kendrick’s digit copying test (P=0.004, r=0.81; n=10), which measures speed of information processing; and (b) 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, Aβ42, while showing no association with Aβ40 levels, amyloid plaque load or tau protein phosphorylation. Finally, high endogenous levels of Aβ42 in APPSWE/Neuro-2a cells directly reduced anandamide and NArPE concentrations in cells lysates. The results suggest that an Aβ42-dependent impairment in brain anandamide mobilization contributes to cognitive dysfunction in AD. © 2011 Elsevier Inc. All rights reserved. *Corresponding Author: Dr. Daniele Piomelli, Department of Pharmacology, 3101 Gillespie NRF, University of California, Irvine, CA 92697-4625. Phone: (949) 824-6180 Fax: (949) 824-6305 piomelli@uci.edu. 1K. -M.J. and G.A. contributed equally to this work. 2Present address: Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA, 40506. Disclosure statement The authors declare no actual or potential conflicts of interest. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript Neurobiol Aging. Author manuscript; available in PMC 2013 August 01. Published in final edited form as: Neurobiol Aging. 2012 August ; 33(8): 1522–1532. doi:10.1016/j.neurobiolaging. 2011.03. 012. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript