title: Deficient liver biosynthesis of docosahexaenoic acid correlates with cognitive impairment in Alzheimer's disease.
abstract: Reduced brain levels of docosahexaenoic acid (C22:6n-3), a neurotrophic and neuroprotective fatty acid, may contribute to cognitive decline in Alzheimer's disease. Here, we investigated whether the liver enzyme system that provides docosahexaenoic acid to the brain is dysfunctional in this disease. Docosahexaenoic acid levels were reduced in temporal cortex, mid-frontal cortex and cerebellum of subjects with Alzheimer's disease, compared to control subjects (P  =  0.007). Mini Mental State Examination (MMSE) scores positively correlated with docosahexaenoic/α-linolenic ratios in temporal cortex (P =  0.005) and mid-frontal cortex (P  =  0.018), but not cerebellum. Similarly, liver docosahexaenoic acid content was lower in Alzheimer's disease patients than control subjects (P  =  0.011). Liver docosahexaenoic/α-linolenic ratios correlated positively with MMSE scores (r  =  0.78; P<0.0001), and negatively with global deterioration scale grades (P  =  0.013). Docosahexaenoic acid precursors, including tetracosahexaenoic acid (C24:6n-3), were elevated in liver of Alzheimer's disease patients (P  =  0.041), whereas expression of peroxisomal d-bifunctional protein, which catalyzes the conversion of tetracosahexaenoic acid into docosahexaenoic acid, was reduced (P  = 0.048). Other genes involved in docosahexaenoic acid metabolism were not affected. The results indicate that a deficit in d-bifunctional protein activity impairs docosahexaenoic acid biosynthesis in liver of Alzheimer's disease patients, lessening the flux of this neuroprotective fatty acid to the brain.
authors.affiliation: Department of Pharmacology, University of California Irvine, Irvine, California, United States of America.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Astarita
authors.forename: Kwang-Mook
authors.initials: KM
authors.lastname: Jung
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Berchtold
authors.forename: Vinh Q
authors.initials: VQ
authors.lastname: Nguyen
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gillen
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Head
authors.forename: Carl W
authors.initials: CW
authors.lastname: Cotman
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000523:psychology*; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D003071:Cognition; D004281:Docosahexaenoic Acids / Q000172:deficiency*; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D009483:Neuropsychological Tests
chemical_list: D004281:Docosahexaenoic Acids