Francesca Bosetti

Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer’s disease

Evidence suggests that mitochondrial dysfunction is prominent in Alzheimers disease (AD). A failure of one or more of the mitochondrial electron transport chain enzymes or of F(1)F(0)-ATPase (ATP synthase) could compromise brain energy stores, generate damaging reactive oxygen species (ROS), and lead to neuronal death. In the present study, cytochrome c oxidase (COX) and F(1)F(0)-ATPase activities of isolated mitochondria from platelets and postmortem motor cortex and hippocampus from AD patients and age-matched control subjects were assayed. Compared with controls, COX activity was decreased significantly in platelets (-30%, P < 0.01, n = 20) and hippocampus (-35 to -40%, P < 0.05, n = 6), but not in motor cortex from the AD patients. In contrast, in AD platelets and brain tissues, F(1)F(0)-ATP hydrolysis activity was not significantly changed. Moreover, the ATP synthesis rate was similar in mitochondria of platelets from AD patients and controls. These results demonstrate that COX but not F(1)F(0)-ATPase is a mitochondrial target in AD, in both a brain association area and in platelets. A reduced COX activity may make the tissue vulnerable to excitotoxicity or reduced oxygen availability.

The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research.

Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prostaglandins and other lipid mediators. Because it can be induced by inflammatory stimuli, COX-2 has been classically considered as the most appropriate target for anti-inflammatory drugs. However, recent data indicate that COX-2 can mediate neuroprotection and that COX-1 is a major player in the neuroinflammatory process. We discuss the specific contributions of COX-1 and COX-2 in various neurodegenerative diseases and in models of neuroinflammation. We suggest that, owing to its predominant localization in microglia, COX-1 might be the major player in neuroinflammation, whereas COX-2, which is localized in neurons, might have a major role in models in which the neurons are directly challenged. Overall, the benefit of using COX-2 inhibitors should be carefully evaluated and COX-1 preferential inhibitors should be further investigated as a potential therapeutic approach in neurodegenerative diseases with an inflammatory component.

Vascular contributions to cognitive impairment and dementia including Alzheimer's disease

Scientific evidence continues to demonstrate the linkage of vascular contributions to cognitive impairment and dementia such as Alzheimers disease. In December, 2013, the Alzheimers Association, with scientific input from the National Institute of Neurological Disorders and Stroke and the National Heart, Lung and Blood Institute from the National Institutes of Health, convened scientific experts to discuss the research gaps in our understanding of how vascular factors contribute to Alzheimers disease and related dementia. This manuscript summarizes the meeting and the resultant discussion, including an outline of next steps needed to move this area of research forward.

Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E(2) concentration in rat brain.

Rats treated with lithium chloride for 6 weeks have been reported to demonstrate reduced turnover of arachidonic acid (AA) in brain phospholipids, and decreases in mRNA and protein levels, and enzyme activity, of AA-selective cytosolic phospholipase A2(cPLA2). We now report that chronic lithium administration to rats significantly reduced the brain protein level and enzyme activity of cyclooxygenase-2 (COX-2), without affecting COX-2 mRNA. Lithium also reduced the brain concentration of prostaglandin E2 (PGE2), a bioactive product of AA formed via the COX reaction. COX-1 and the Ca2+-independent iPLA2 (type VI) were unaffected by lithium. These and prior results indicate that lithium targets a part of the AA cascade that involves cPLA2 and COX-2. This effect may contribute to lithiums therapeutic action in bipolar disorder.

Genetic deletion or pharmacological inhibition of cyclooxygenase-1 attenuate lipopolysaccharide-induced inflammatory response and brain injury.

Cyclooxygenase (COX) ‐1 and ‐2 metabolize arachidonic acid to prostanoids and reactive oxygen species, major μlayers in the neuroinflammatory process. While most reports have focused on the inducible isoform, COX‐2, the contribution of COX‐1 to the inflammatory response is unclear. In the present study, the contribution of COX‐1 in the neuroinflammatory response to intracerebroventricular lipopolysaccharide (LPS) was investigated using COX‐1 deficient (COX‐ 1−/−) mice or wild‐type (COX‐1+/+) mice pretreated with SC‐560, a selective COX‐1 inhibitor. Twenty‐four hours after lipopolysaccharide (LPS) injection, COX‐ 1−/− mice showed decreased protein oxidation and LPS‐induced neuronal damage in the hippocampus compared with COX‐1+/+ mice. COX‐1−/−mice showed a significant reduction of microglial activation, proinflammatory mediators, and expression of COX‐2, inducible NOS, and NADPH oxidase. The transcriptional down‐regulation of cytokines and other inflammatory markers in COX‐1−/−mice was mediated by a reduced activation of NF‐κB and signal transducer and activator of transcription 3. Administration of SC‐560 prior to LPS injection also attenuated the neuroinflammatory response by decreasing brain levels of prostaglandin (PG)E2, PGD2, PGF2h, and thromboxane B2, as well as the expression of proinflammatory cytokines and chemokine. These findings suggest that COX‐1 μlays a previously unrecognized role in neuroinflammatory damage.—Choi, S‐H., Langenbach, R., Bosetti, F. Genetic deletion or pharmacological inhibition of cyclooxygenase‐1 attenuate lipopolysaccharide‐induced inflammatory response and brain injury. FASEB J. 22, 1491–1501 (2008)

The contribution of myelin to magnetic susceptibility-weighted contrasts in high-field MRI of the brain.

T(2)*-weighted gradient-echo MRI images at high field (≥ 7T) have shown rich image contrast within and between brain regions. The source for these contrast variations has been primarily attributed to tissue magnetic susceptibility differences. In this study, the contribution of myelin to both T(2)* and frequency contrasts is investigated using a mouse model of demyelination based on a cuprizone diet. The demyelinated brains showed significantly increased T(2)* in white matter and a substantial reduction in gray-white matter frequency contrast, suggesting that myelin is a primary source for these contrasts. Comparison of in-vivo and in-vitro data showed that, although tissue T(2)* values were reduced by formalin fixation, gray-white matter frequency contrast was relatively unaffected and fixation had a negligible effect on cuprizone-induced changes in T(2)* and frequency contrasts.

Inhibition of NADPH oxidase promotes alternative and anti–inflammatory microglial activation during neuroinflammation

J. Neurochem. (2012) 120, 292–301.

Targeting cyclooxygenases-1 and -2 in neuroinflammation: Therapeutic implications

Neuroinflammation has been implicated in the pathogenesis or the progression of a variety of acute and chronic neurological and neurodegenerative disorders, including Alzheimers disease. Prostaglandin H synthases or cyclooxygenases (COX -1 and COX-2) play a central role in the inflammatory cascade by converting arachidonic acid into bioactive prostanoids. In this review, we highlighted recent experimental data that challenge the classical view that the inducible isoform COX-2 is the most appropriate target to treat neuroinflammation. First, we discuss data showing that COX-2 activity is linked to anti-inflammatory and neuroprotective actions and is involved in the generation of novel lipid mediators with pro-resolution properties. Then, we review recent data demonstrating that COX-1, classically viewed as the homeostatic isoform, is actively involved in brain injury induced by pro-inflammatory stimuli including Aβ, lipopolysaccharide, IL-1β, and TNF-α. Overall, we suggest revisiting the traditional views on the roles of each COX during neuroinflammation and we propose COX-1 inhibition as a viable therapeutic approach to treat CNS diseases with a marked inflammatory component.

Effects of neuroinflammation on the regenerative capacity of brain stem cells.

J. Neurochem. (2011) 116, 947–956.

Rat brain arachidonic acid metabolism is increased by a 6-day intracerebral ventricular infusion of bacterial lipopolysaccharide

Palmitate (16:0) 80.2 ± 10.9 81.9 ± 10.9 26.2 ± 0.3 27.0 ± 1.1 11.2 ± 2.6 13.4 ± 3.9 Stearate (18:0) 26.8 ± 4.3 24.6 ± 2.8 48.0 ± 8.0 59.0 ± 9.2 1.9 ± 1.5 3.2 ± 1.8 Oleate (18:1n-9) 35.3 ± 10.0 37.5 ± 8.4 36.6 ± 4.9 38.8 ± 1.4 10.6 ± 3.1 11.7 ± 3.3 Linoleate (18:2n-6) 38.5 ± 10.6 39.8 ± 7.5 1.8 ± 0.2 *3.7 ± 0.3 4.0 ± 1.2 5.5 ± 3.9 Arachidonate (20:4n-6) 8.9 ± 2.8 6.2 ± 1.8 8.2 ± 0.1 *19.7 ± 3.6 0.7 ± 0.3 0.5 ± 0.4 Docosahexaenoate (22:6n-3) 8.7 ± 3.2 8.1 ± 2.9 1.2 ± 0.8 1.7 ± 0.2 0.6 ± 0.3 0.8 ± 0.3