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1.
J Am Coll Cardiol ; 74(15): 1910-1923, 2019 10 15.
Article in English | MEDLINE | ID: mdl-31601371

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with important vascular and hemostatic alterations that should be taken into account during diagnosis and treatment. OBJECTIVES: This study evaluates whether anticoagulation with dabigatran, a clinically approved oral direct thrombin inhibitor with a low risk of intracerebral hemorrhage, ameliorates AD pathogenesis in a transgenic mouse model of AD. METHODS: TgCRND8 AD mice and their wild-type littermates were treated for 1 year with dabigatran etexilate or placebo. Cognition was evaluated using the Barnes maze, and cerebral perfusion was examined by arterial spin labeling. At the molecular level, Western blot and histochemical analyses were performed to analyze fibrin content, amyloid burden, neuroinflammatory activity, and blood-brain barrier (BBB) integrity. RESULTS: Anticoagulation with dabigatran prevented memory decline, cerebral hypoperfusion, and toxic fibrin deposition in the AD mouse brain. In addition, long-term dabigatran treatment significantly reduced the extent of amyloid plaques, oligomers, phagocytic microglia, and infiltrated T cells by 23.7%, 51.8%, 31.3%, and 32.2%, respectively. Dabigatran anticoagulation also prevented AD-related astrogliosis and pericyte alterations, and maintained expression of the water channel aquaporin-4 at astrocytic perivascular endfeet of the BBB. CONCLUSIONS: Long-term anticoagulation with dabigatran inhibited thrombin and the formation of occlusive thrombi in AD; preserved cognition, cerebral perfusion, and BBB function; and ameliorated neuroinflammation and amyloid deposition in AD mice. Our results open a field for future investigation on whether the use of direct oral anticoagulants might be of therapeutic value in AD.


Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Dabigatran/administration & dosage , Amyloid/metabolism , Amyloid beta-Peptides/metabolism , Animals , Anticoagulants/administration & dosage , Blood-Brain Barrier , Cerebral Cortex/metabolism , Disease Models, Animal , Female , Fibrin/metabolism , Hemostasis , Hippocampus/metabolism , Maze Learning , Memory , Mice , Mice, Transgenic , Neurodegenerative Diseases/physiopathology , Perfusion , Thrombosis
2.
J Exp Med ; 211(6): 1049-62, 2014 Jun 02.
Article in English | MEDLINE | ID: mdl-24821909

ABSTRACT

Many Alzheimer's disease (AD) patients suffer from cerebrovascular abnormalities such as altered cerebral blood flow and cerebral microinfarcts. Recently, fibrinogen has been identified as a strong cerebrovascular risk factor in AD, as it specifically binds to ß-amyloid (Aß), thereby altering fibrin clot structure and delaying clot degradation. To determine if the Aß-fibrinogen interaction could be targeted as a potential new treatment for AD, we designed a high-throughput screen and identified RU-505 as an effective inhibitor of the Aß-fibrinogen interaction. RU-505 restored Aß-induced altered fibrin clot formation and degradation in vitro and inhibited vessel occlusion in AD transgenic mice. Furthermore, long-term treatment of RU-505 significantly reduced vascular amyloid deposition and microgliosis in the cortex and improved cognitive impairment in mouse models of AD. Our studies suggest that inhibitors targeting the Aß-fibrinogen interaction show promise as therapy for treating AD.


Subject(s)
Alzheimer Disease/drug therapy , Amyloid beta-Peptides/metabolism , Cognition Disorders/prevention & control , Fibrinogen/metabolism , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Small Molecule Libraries/pharmacology , Thrombosis/prevention & control , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Humans , Maze Learning/drug effects , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Fluorescence , Molecular Structure , Motor Activity/drug effects , Protein Binding/drug effects , Pyrazoles/chemistry , Pyrimidines/chemistry , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacokinetics , Time-Lapse Imaging/methods
3.
Ultrasound Obstet Gynecol ; 27(5): 571-3, 2006 May.
Article in English | MEDLINE | ID: mdl-16570265

ABSTRACT

We report a case of fetal nasal glioma diagnosed at 21 weeks of gestation. The glioma appeared as a moderately hypoechoic mass arising from the junction between the medial aspect of the left orbit and the lateral aspect of the nose, and showing no internal vascularization on color and power Doppler ultrasonography. Fetal magnetic resonance imaging (MRI) excluded the possibility of an encephalocele by ruling out underlying bone defects. After an uneventful pregnancy, the nasal glioma was resected without complications at 4 months of age. The differential diagnosis of fetal paranasal facial masses is discussed.


Subject(s)
Glioma/diagnostic imaging , Nose Neoplasms/diagnostic imaging , Ultrasonography, Doppler, Color , Ultrasonography, Prenatal/methods , Adult , Female , Glioma/diagnosis , Glioma/embryology , Humans , Infant, Newborn , Magnetic Resonance Imaging , Nose Neoplasms/diagnosis , Nose Neoplasms/embryology , Pregnancy , Pregnancy Trimester, Second
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