Non-alcoholic fatty liver disease, and the underlying altered fatty acid metabolism, reveals brain hypoperfusion and contributes to the cognitive decline in APP/PS1 mice

Non-alcoholic fatty liver disease (NAFLD), the leading cause of chronic liver disease, is associated with cognitive decline in middle-aged adults, but the mechanisms underlying this association are not clear. We hypothesized that NAFLD would unveil the appearance of brain hypoperfusion in association with altered plasma and brain lipid metabolism. To test our hypothesis, amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mice were fed a standard diet or a high-fat, cholesterol and cholate diet, inducing NAFLD without obesity and hyperglycemia. The diet-induced NAFLD disturbed monounsaturated and polyunsaturated fatty acid (MUFAs, PUFAs) metabolism in the plasma, liver, and brain, and particularly reduced n-3 PUFAs levels. These alterations in lipid homeostasis were associated in the brain with an increased expression of Tnfalpha, Cox2, p21, and Nox2, reminiscent of brain inflammation, senescence, and oxidative stress. In addition, compared to wild-type (WT) mice, while brain perfusion was similar in APP/PS1 mice fed with a chow diet, NAFLD in APP/PS1 mice reveals cerebral hypoperfusion and furthered cognitive decline. NAFLD reduced plasma beta40- and beta42-amyloid levels and altered hepatic but not brain expression of genes involved in beta-amyloid peptide production and clearance. Altogether, our results suggest that in a mouse model of Alzheimer disease (AD) diet-induced NAFLD contributes to the development and progression of brain abnormalities through unbalanced brain MUFAs and PUFAs metabolism and cerebral hypoperfusion, irrespective of brain amyloid pathology that may ultimately contribute to the pathogenesis of AD

Activation of cAMP signaling transiently inhibits apoptosis in vascular smooth muscle cells in a site upstream of caspase-3

Intracellular signaling pathways that are involved in protection of vascular smooth muscle cells (VSMC) from apoptosis remain poorly understood. This study examines the effect of activators of cAMP/cGMP signaling on apoptosis in non-transfected VSMC and in VSMC transfected with c-myc (VSMC-MYC) or with its functional analogue, E1A-adenoviral protein (VSMC-E1A). Serum-deprived VSMC-E1A exhibited the highest apoptosis measured as the content of chromatin and low molecular weight DNA fragments, phosphatidylserine content in the outer surface of plasma membrane and caspase-3 activity (ten-, five-, four- and tenfold increase after 6 h of serum withdrawal, respectively). In VSMC-E1A, the addition of an activator of adenylate cyclase, forskolin, abolished chromatin cleavage, DNA laddering, caspase-3 activation and the appearance of morphologically-defined apoptotic cells triggered by 6 h of serum deprivation. In non-transfected VSMC and in VSMC-MYC, 6 h serum deprivation led to approximately six- and threefold activation of chromatin cleavage, respectively, that was also blocked by forskolin. In VSMC-E1A, inhibition of apoptosis was observed with other activators of cAMP signaling (cholera toxin, isoproterenol, adenosine, 8-Br-cAMP), whereas 6 h incubation with modulators of cGMP signaling (8-Br-cGMP, nitroprusside, atrial natriuretic peptide, L-NAME) did not affect the development of apoptotic machinery. The antiapoptotic effect of forskolin was abolished in 24 h of serum deprivation that was accompanied by normalization of intracellular cAMP content and protein kinase A (PKA) activity. Protection of VSMC-E1A from apoptosis by forskolin was blunted by PKA inhibitors (H-89 and KT5720), whereas transfection of cells with PKA catalytic subunit attenuated apoptosis triggered by serum withdrawal. The protection of VSMC-E1A by forskolin from apoptosis was insensitive to modulators of cytoskeleton assembly (cytochalasin B, colchicine). Neither acute (30 min) nor chronic (24 h) exposure of VSMC to forskolin modified basal and serum-induced phosphorylation of the MAP kinase ERK1/2. Thus, our results show that activation of cAMP signaling delays the development of apoptosis in serum-deprived VSMC at a site upstream of caspase-3 via activation of PKA and independently of cAMP-induced reorganization of the cytoskeleton network and the ERK1/2-terminated MAPK signaling cascade

3D Reconstruction of the Neurovascular Unit Reveals Differential Loss of Cholinergic Innervation in the Cortex and Hippocampus of the Adult Mouse Brain

Increasing evidence supports a role for cerebrovasculature dysfunction in the etiology of Alzheimer’s disease (AD). Blood vessels in the brain are composed of a collection of cells and acellular material that comprise the neurovascular unit (NVU). The NVU in the hippocampus and cortex receives innervation from cholinergic neurons that originate in the basal forebrain. Death of these neurons and their nerve fibers is an early feature of AD. However, the effect of the loss of cholinergic innervation on the NVU is not well characterized. The purpose of this study was to evaluate the effect of the loss of cholinergic innervation of components of the NVU at capillaries, arteries and veins in the hippocampus and cortex. Adult male C57BL/6 mice received an intracerebroventricular injection of the immunotoxin p75NTR mu-saporin to induce the loss of cholinergic neurons. Quadruple labeling immunohistochemistry and 3D reconstruction were carried out to characterize specific points of contact between cholinergic fibers and collagen IV, smooth muscle cells and astrocyte endfeet. Innate differences were observed between vessels of the hippocampus and cortex of control mice, including a greater amount of cholinergic contact with perivascular astrocytes in hippocampal capillaries and a thicker basement membrane in hippocampal veins. Saporin treatment induced a loss of cholinergic innervation at the arterial basement membrane and smooth muscle cells of both the hippocampus and the cortex. In the cortex, there was an additional loss of innervation at the astrocytic endfeet. The current results suggest that cortical arteries are more strongly affected by cholinergic denervation than arteries in the hippocampus. This regional variation may have implications for the etiology of the vascular pathology that develops in AD

High Circulating Levels of ANGPTL2: Beyond a Clinical Marker of Systemic Inflammation

Angiopoietin-like 2 (ANGPTL2) is a proinflammatory protein belonging to the angiopoietin-like family. ANGPTL2 is secreted and detected in the systemic circulation. Different observational clinical studies reported that circulating levels of ANGPTL2 increase significantly in various chronic inflammatory diseases and showed associations between ANGPTL2 levels and diagnosis and/or prognosis of cardiovascular diseases, diabetes, chronic kidney disease, and various types of cancers. However, these studies did not address the following questions: (a) what are the sources of circulating ANGPTL2? (b) How and by which mechanisms an increase in circulating ANGPTL2 contributes to the pathogenesis of chronic inflammatory diseases? (c) Does an increase in circulating levels of ANGPTL2 measured in a well-defined chronic medical condition originate from a specific cell type? Mechanistic hypotheses have been proposed based on studies performed in mice and cultured cells, and proinflammatory, prooxidative, proangiogenic, proliferative, and antiapoptotic properties of ANGPTL2 have been reported. The aim of this review is to propose answers concerning the potential sources of circulating ANGPTL2 and its common pathological properties associated with various chronic inflammatory diseases and death in humans. We believe that high circulating ANGPTL2 levels are more than an inflammatory marker and may reflect the senescent cellular load of an individual

Angptl2 is a Marker of Cellular Senescence: The Physiological and Pathophysiological Impact of Angptl2-Related Senescence

Cellular senescence is a cell fate primarily induced by DNA damage, characterized by irreversible growth arrest in an attempt to stop the damage. Senescence is a cellular response to a stressor and is observed with aging, but also during wound healing and in embryogenic developmental processes. Senescent cells are metabolically active and secrete a multitude of molecules gathered in the senescence-associated secretory phenotype (SASP). The SASP includes inflammatory cytokines, chemokines, growth factors and metalloproteinases, with autocrine and paracrine activities. Among hundreds of molecules, angiopoietin-like 2 (angptl2) is an interesting, although understudied, SASP member identified in various types of senescent cells. Angptl2 is a circulatory protein, and plasma angptl2 levels increase with age and with various chronic inflammatory diseases such as cancer, atherosclerosis, diabetes, heart failure and a multitude of age-related diseases. In this review, we will examine in which context angptl2 was identified as a SASP factor, describe the experimental evidence showing that angptl2 is a marker of senescence in vitro and in vivo, and discuss the impact of angptl2-related senescence in both physiological and pathological conditions. Future work is needed to demonstrate whether the senescence marker angptl2 is a potential clinical biomarker of age-related diseases

Âge et stress oxydant

Différents mécanismes cellulaires de réparation, de défense et de maintien de l’homéostasie sont continuellement activés au cours de la vie. Ils permettent d’établir un équilibre temporaire face aux agressions successives endogènes et exogènes. Le principe d’hormesis