Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA2β (VIA)-deficient mice

Basselin, Mireille; Rosa, Ana Cláudia Ferreira; Ramadan, Epolia; Cheon, Yewon; Chang, Lisa; Chen, Mei; Greenstein, Deanna; Wohltmann, Mary; Turk, John; Rapoport, Stanley I.

doi:10.1194/jlr.m008334

Cited by 55 publications

(52 citation statements)

References 67 publications

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“…For example, k* was decreased in mice genetically lacking calcium-independent PLA 2 β VIA [27], but it was increased when plasma and brain DHA concentrations were reduced by chronic dietary ω-3 PUFA deprivation in rats [17] or in subjects with chronic alcoholism during acute withdrawal of alcohol [22]. Moreover, the DHA transport coefficient was decreased with long-term high-DHA dietary consumption [28].…”

Section: Discussionmentioning

confidence: 95%

[P3–317]: DHA BRAIN UPTAKE AND APOE4 STATUS: A PET STUDY WITH [1‐¹¹C]‐DHA

Yassine

Croteau

Rawat

et al. 2017

Alzheimer's & Dementia

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Background: The apolipoprotein E ɛ4 (APOE4) allele is the strongest genetic risk factor identified for developing Alzheimer's disease (AD). Among brain lipids, alteration in the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) homeostasis is implicated in AD pathogenesis. APOE4 may influence both brain DHA metabolism and cognitive outcomes. Methods: Using positron emission tomography, regional incorporation coefficients (k*), rates of DHA incorporation from plasma into the brain using [1-11 C]-DHA (J in ), and regional cerebral blood flow using [ 15 O]-water were measured in 22 middle-aged healthy adults (mean age 35 years, range 19-65 years). Data were partially volume error-corrected for brain atrophy. APOE4 phenotype was determined by protein expression, and unesterified DHA concentrations were quantified in plasma. An exploratory post hoc analysis of the effect of APOE4 on DHA brain kinetics was performed. Results: The mean global gray matter DHA incorporation coefficient, k*, was significantly higher (16%) among APOE4 carriers (n = 9) than among noncarriers (n = 13, p = 0.046). Higher DHA incorporation coefficients were observed in several brain regions, particularly in the entorhinal subregion, an area affected early in AD pathogenesis. Cerebral blood flow, unesterified plasma DHA, and whole brain DHA incorporation rate (J in ) did not differ significantly between the APOE groups.

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Section: Discussionmentioning

confidence: 95%

[P3–317]: DHA BRAIN UPTAKE AND APOE4 STATUS: A PET STUDY WITH [1‐¹¹C]‐DHA

Yassine

Croteau

Rawat

et al. 2017

Alzheimer's & Dementia

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“…Conversely, the net rate of LA release from brain phospholipids, including CLs, is at least five times lower than that of DHA (22:6n-3) from PC (Green et al, 2008), suggesting the importance of iPLA 2 ␤ for enzymatic release of DHA from PC within the brain. IMS demonstrated a prominent increase of DHA-containing PC in the gray matter, especially the posterior horn, which would have resulted from compensatory production of phospholipids in a background of membrane degeneration and lack of acyl decomposition in PC attributable to iPLA 2 ␤ deficiency (Basselin et al, 2010). DHA is one of the important PUFAs (Green et al, 2008), possessing double-or triple-bond carbon chains and accounting for the water solubility and liquefaction of membranes (Stillwell and Wassell, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…The functions of iPLA 2 ␤ include remodeling of membrane phospholipids (Balsinde et al, 1997), fatty acid oxidation (Strokin et al, 2003), release of docosahexaenoic acid (DHA) and arachidonic acid (AA) (Green et al, 2008), cell growth and signaling (Hooks and Cumming, 2008), and cell death (Shinzawa and Tsujimoto, 2003). In the brain of iPLA 2 ␤-deficient mice, DHA metabolism is reduced at 4 months without overt neuropathology (Basselin et al, 2010), and an iPLA 2 ␤ inhibitor has been reported to attenuate linoleic acid (LA) incorporation of cardiolipin (CL) in rat heart (Zachman et al, 2010). In monkey brain, iPLA 2 ␤ is localized in axon terminals and dendritic spines of neurons (Ong et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A₂β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes

Beck¹,

Sugiura²,

et al. 2011

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Infantile neuroaxonal dystrophy (INAD) is a fatal neurodegenerative disease characterized by the widespread presence of axonal swellings (spheroids) in the CNS and PNS and is caused by gene abnormality in PLA2G6[calcium-independent phospholipase A 2 ␤ (iPLA 2 ␤)], which is essential for remodeling of membrane phospholipids. To clarify the pathomechanism of INAD, we pathologically analyzed the spinal cords and sciatic nerves of iPLA 2 ␤ knock-out (KO) mice, a model of INAD. At 15 weeks (preclinical stage), periodic acid-Schiff (PAS)-positive granules were frequently observed in proximal axons and the perinuclear space of large neurons, and these were strongly positive for a marker of the mitochondrial outer membrane and negative for a marker of the inner membrane. By 100 weeks (late clinical stage), PAS-positive granules and spheroids had increased significantly in the distal parts of axons, and ultrastructural examination revealed that these granules were, in fact, mitochondria with degenerative inner membranes. Collapse of mitochondria in axons was accompanied by focal disappearance of the cytoskeleton. Partial membrane loss at axon terminals was also evident, accompanied by degenerative membranes in the same areas. Imaging mass spectrometry showed a prominent increase of docosahexaenoic acidcontaining phosphatidylcholine in the gray matter, suggesting insufficient membrane remodeling in the presence of iPLA 2 ␤ deficiency. Prominent axonal degeneration in neuroaxonal dystrophy might be explained by the collapse of abnormal mitochondria after axonal transportation. Insufficient remodeling and degeneration of mitochondrial inner membranes and presynaptic membranes appear to be the cause of the neuroaxonal dystrophy in iPLA 2 ␤-KO mice.

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“…In vertebrates, the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA, 22:6n-3) is thought to play antioxidant, neuroprotective, and neurotransmission roles in brain [1–4]. DHA must be obtained directly from the diet or by liver synthesis from its dietary essential precursor, α-linolenic acid (α-LNA, 18:3 n-3) [5].…”

Section: Introductionmentioning

confidence: 99%

iPLA2β Knockout Mouse, a Genetic Model for Progressive Human Motor Disorders, Develops Age-Related Neuropathology

et al. 2014

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Calcium-independent phospholipase A2 group VIa (iPLA2β) preferentially releases docosahexaenoic acid (DHA) from the sn-2 position of phospholipids. Mutations of its gene, PLA2G6, are found in patients with several progressive motor disorders, including Parkinson disease. At 4 months, PLA2G6 knockout mice (iPLA2β−/−) show minimal neuropathology but altered brain DHA metabolism. By 1 year, they develop motor disturbances, cerebellar neuronal loss, and striatal α-synuclein accumulation. We hypothesized that older iPLA2β−/− mice also would exhibit inflammatory and other neuropathological changes. Real-time polymerase chain reaction and Western blotting were performed on whole brain homogenate from 15 to 20-month old male iPLA2β−/− or wild-type (WT) mice. These older iPLA2β−/− mice compared with WT showed molecular evidence of microglial (CD-11b, iNOS) and astrocytic (glial fibrillary acidic protein) activation, disturbed expression of enzymes involved in arachidonic acid metabolism, loss of neuroprotective brain derived neurotrophic factor, and accumulation of cytokine TNF-α messenger ribonucleic acid, consistent with neuroinflammatory pathology. There was no evidence of synaptic loss, of reduced expression of dopamine active reuptake transporter, or of accumulation of the Parkinson disease markers Parkin or Pink1. iPLA2γ expression was unchanged. iPLA2β deficient mice show evidence of neuroinflammation and associated neuropathology with motor dysfunction in later life. These pathological biomarkers could be used to assess efficacy of dietary intervention, antioxidants or other therapies on disease progression in this mouse model of progressive human motor diseases associated with a PLA2G6 mutation.

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Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA2β (VIA)-deficient mice

Cited by 55 publications

References 67 publications

[P3–317]: DHA BRAIN UPTAKE AND APOE4 STATUS: A PET STUDY WITH [1‐¹¹C]‐DHA

[P3–317]: DHA BRAIN UPTAKE AND APOE4 STATUS: A PET STUDY WITH [1‐¹¹C]‐DHA

Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A₂β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes

iPLA2β Knockout Mouse, a Genetic Model for Progressive Human Motor Disorders, Develops Age-Related Neuropathology

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Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA2β (VIA)-deficient mice

Cited by 55 publications

References 67 publications

[P3–317]: DHA BRAIN UPTAKE AND APOE4 STATUS: A PET STUDY WITH [1‐11C]‐DHA

[P3–317]: DHA BRAIN UPTAKE AND APOE4 STATUS: A PET STUDY WITH [1‐11C]‐DHA

Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A2β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes

iPLA2β Knockout Mouse, a Genetic Model for Progressive Human Motor Disorders, Develops Age-Related Neuropathology

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[P3–317]: DHA BRAIN UPTAKE AND APOE4 STATUS: A PET STUDY WITH [1‐¹¹C]‐DHA

[P3–317]: DHA BRAIN UPTAKE AND APOE4 STATUS: A PET STUDY WITH [1‐¹¹C]‐DHA

Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A₂β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes