RESUMEN
Deep perforator arteriopathy (DPA) and cerebral amyloid angiopathy (CAA) are the commonest known cerebral small vessel diseases (CSVD), which cause ischaemic stroke, intracebral haemorrhage (ICH) and vascular cognitive impairment (VCI). While thus far mainly considered as separate entities, we here propose that DPA and CAA share similarities, overlap and interact, so that 'pure' DPA or CAA are extremes along a continuum of age-related small vessel pathologies. We suggest blood-brain barrier (BBB) breakdown, endothelial damage and impaired perivascular ß-amyloid (Aß) drainage are hallmark common mechanisms connecting DPA and CAA. We also suggest a need for new biomarkers (e.g. high-resolution imaging) to deepen understanding of the complex relationships between DPA and CAA.
Asunto(s)
Envejecimiento/patología , Enfermedades de los Pequeños Vasos Cerebrales/patología , Péptidos beta-Amiloides/metabolismo , Animales , Femenino , Humanos , MasculinoRESUMEN
AIMS: Apolipoprotein A-I (apoA-I), the principal apolipoprotein associated with high-density lipoproteins in the periphery, is also found at high concentrations in the cerebrospinal fluid. Previous studies have reported either no impact or vascular-specific effects of apoA-I knockout (KO) on ß-amyloid (Aß) pathology. However, the putative mechanism(s) by which apoA-I may influence Aß deposition is unknown. METHODS: We evaluated the effect of apoA-I deletion on Aß pathology, Aß production and clearance from the brain in the Tg2576 mouse model of Alzheimer's disease (AD). RESULTS: Contrary to previous reports, deletion of the APOA1 gene significantly reduced concentrations of insoluble Aß40 and Aß42 and reduced plaque load in both the parenchyma and blood vessels of apoA-I KO × Tg2576 mice compared to Tg2576 animals. This was not due to decreased Aß production or alterations in Aß species. Levels of soluble clusterin/apoJ were significantly higher in neurons of apoA-I KO mice compared to both wildtype (WT) and apoA-I KO × Tg2576 mice. In addition, clearance of Aß along intramural periarterial drainage pathways was significantly higher in apoA-I KO mice compared to WT animals. CONCLUSION: These data suggest that deletion of apoA-I is associated with increased clearance of Aß and reduced parenchymal and vascular Aß pathology in the Tg2576 model. These results suggest that peripheral dyslipidaemia can modulate the expression of apolipoproteins in the brain and may influence Aß clearance and aggregation in AD.
Asunto(s)
Enfermedad de Alzheimer/patología , Apolipoproteína A-I/genética , Encéfalo/patología , Placa Amiloide/patología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Placa Amiloide/genética , Placa Amiloide/metabolismoRESUMEN
AIMS: Amyloid beta (Aß) accumulation in the walls of leptomeningeal arteries as cerebral amyloid angiopathy (CAA) is a major feature of Alzheimer's disease. In this study, we used global quantitative proteomic analysis to examine the hypothesis that the leptomeningeal arteries derived from patients with CAA have a distinct endophenotypic profile compared to those from young and elderly controls. METHODS: Freshly dissected leptomeningeal arteries from the Newcastle Brain Tissue Resource and Edinburgh Sudden Death Brain Bank from seven elderly (82.9 ± 7.5 years) females with severe capillary and arterial CAA, as well as seven elderly (88.3 ± 8.6 years) and five young (45.4 ± 3.9 years) females without CAA were used in this study. Arteries from four patients with CAA, two young and two elderly controls were individually analysed using quantitative proteomics. Key proteomic findings were then validated using immunohistochemistry. RESULTS: Bioinformatics interpretation of the results showed a significant enrichment of the immune response/classical complement and extracellular matrix remodelling pathways (P < 0.05) in arteries affected by CAA vs. those from young and elderly controls. Clusterin (apolipoprotein J) and tissue inhibitor of metalloproteinases-3 (TIMP3), validated using immunohistochemistry, were shown to co-localize with Aß and to be up-regulated in leptomeningeal arteries from CAA patients compared to young and elderly controls. CONCLUSIONS: Global proteomic profiling of brain leptomeningeal arteries revealed that clusterin and TIMP3 increase in leptomeningeal arteries affected by CAA. We propose that clusterin and TIMP3 could facilitate perivascular clearance and may serve as novel candidate therapeutic targets for CAA.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/metabolismo , Angiopatía Amiloide Cerebral/metabolismo , Clusterina/metabolismo , Inhibidor Tisular de Metaloproteinasa-3/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Arterias/metabolismo , Encéfalo/inmunología , Encéfalo/patología , Angiopatía Amiloide Cerebral/inmunología , Angiopatía Amiloide Cerebral/patología , Vía Clásica del Complemento , Biología Computacional , Endofenotipos , Matriz Extracelular/metabolismo , Femenino , Humanos , Persona de Mediana Edad , ProteómicaRESUMEN
Beta-amyloid accumulation within arterial walls in cerebral amyloid angiopathy is associated with the onset of Alzheimer's disease. However, the mechanism of beta-amyloid clearance along peri-arterial pathways in the brain is not well understood. In this study, we investigate a transport mechanism in the arterial basement membrane consisting of forward-propagating waves and their reflections. The arterial basement membrane is modeled as a periodically deforming annulus filled with an incompressible single-phase Newtonian fluid. A reverse flow, which has been suggested in literature as a beta-amyloid clearance pathway, can be induced by the motion of reflected boundary waves along the annular walls. The wave amplitude and the volume of the annular region govern the flow magnitude and may have important implications for an aging brain. Magnitudes of transport obtained from control volume analysis and numerical solutions of the Navier-Stokes equations are presented.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Encéfalo/irrigación sanguínea , Modelos Biológicos , Péptidos beta-Amiloides/metabolismo , Arterias/metabolismo , Angiopatía Amiloide Cerebral/fisiopatología , Drenaje , Humanos , HidrodinámicaRESUMEN
Epidemiological studies suggest an association between maternal obesity and adverse neurodevelopmental outcomes in offspring. Our aim was to compare the global proteomic portrait in the cerebral cortex between mice born to mothers on a high-fat or control diet who themselves were fed a high-fat or control diet. Male mice born to dams fed a control (C) or high-fat (H) diet 4 weeks before conception and during gestation, and lactation were assigned to either C or H diet at weaning. Mice were killed at 19 weeks and their cerebral cortices were analysed using a two-dimensional liquid chromatography-mass spectrometry methodology. In total, 6 695 proteins were identified (q<0.01), 10% of which were modulated in at least one of the groups relative to controls. In silico analysis revealed that mice clustered based on the diet of the mother and not their own diet and that maternal high-fat diet was significantly associated with response to hypoxia/oxidative stress and apoptosis in the cerebral cortex of the adult offspring. Maternal high-fat diet resulted in distinct endophenotypic changes of the adult offspring cerebral cortex independent of its current diet. The identified proteins could represent novel therapeutic targets for the prevention of neuropathological features resulting from maternal obesity.
Asunto(s)
Corteza Cerebral/patología , Fenómenos Fisiológicos Nutricionales de los Animales , Animales , Dieta Alta en Grasa , Susceptibilidad a Enfermedades , Metabolismo Energético , Femenino , Regulación de la Expresión Génica , Masculino , Fenómenos Fisiologicos Nutricionales Maternos , Ratones , Madres , Embarazo , Efectos Tardíos de la Exposición Prenatal , ProteómicaRESUMEN
Immunological privilege appears to be a product of unique lymphatic drainage systems for the brain and receptor-mediated entry of inflammatory cells through the blood-brain barrier. Most organs of the body have well-defined lymphatic vessels that carry extracellular fluid, antigen presenting cells, lymphocytes, neoplastic cells and even bacteria to regional lymph nodes. The brain has no such conventional lymphatics, but has perivascular pathways that drain interstitial fluid (ISF) from brain parenchyma and cerebrospinal fluid (CSF) from the subarachnoid space to cervical lymph nodes. ISF and solutes drain along narrow, â¼100 nm-thick basement membranes within the walls of cerebral capillaries and arteries to cervical lymph nodes; this pathway does not allow traffic of lymphocytes or antigen presenting cells from brain to lymph nodes. Although CSF drains into blood through arachnoid villi, CSF also drains from the subarachnoid space through channels in the cribriform plate of the ethmoid bone into nasal lymphatics and thence to cervical lymph nodes. This pathway does allow the traffic of lymphocytes and antigen presenting cells from CSF to cervical lymph nodes. Efferent pathways by which lymphocytes enter the brain are regulated by selected integrins on lymphocytes and selective receptors on vascular endothelial cells. Here we review: (1) the structure and function of afferent lymphatic drainage of ISF and CSF, (2) mechanisms involved in the efferent pathways by which lymphocytes enter the brain and (3) the failure of lymphatic drainage of the brain parenchyma with age and the role of such failure in the pathogenesis of Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/inmunología , Encéfalo/inmunología , Sistema Linfático/inmunología , Linfocitos/inmunología , Animales , Líquido Cefalorraquídeo/fisiología , Líquido Extracelular/fisiología , HumanosRESUMEN
Failure of elimination of proteins from the brain is a major feature in many neurodegenerative diseases. Insoluble proteins accumulate in brain parenchyma and in walls of cerebral capillaries and arteries. Cerebral amyloid angiopathy (CAA) is a descriptive term for amyloid in vessel walls. Here, we adopt the term protein elimination failure angiopathy (PEFA) to focus on mechanisms involved in the pathogenesis of a spectrum of disorders that exhibit both unique and common features of protein accumulation in blood vessel walls. We review (a) normal pathways and mechanisms by which proteins and other soluble metabolites are eliminated from the brain along 100- to 150-nm-thick basement membranes in walls of cerebral capillaries and arteries that serve as routes for lymphatic drainage of the brain; (b) a spectrum of proteins involved in PEFA; and (c) changes that occur in artery walls and contribute to failure of protein elimination. We use accumulation of amyloid beta (Aß), prion protein and granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as examples of different factors involved in the aetiology and pathogenesis of PEFA. Finally, we discuss how knowledge of factors involved in PEFA may help to focus on new therapies for neurodegenerative diseases. When Aß (following immunotherapy) and prion protein are released from brain parenchyma they deposit in walls of cerebral capillaries and arteries; GOM in CADASIL accumulates primarily in artery walls. Therefore, the focus of therapy for protein clearance in neurodegenerative disease should perhaps be on facilitating perivascular elimination of proteins and reducing PEFA.
Asunto(s)
CADASIL/etiología , Angiopatía Amiloide Cerebral/etiología , Enfermedades Arteriales Cerebrales/etiología , Enfermedades Neurodegenerativas/terapia , Enfermedades por Prión/etiología , Proteínas Amiloidogénicas/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/patología , CADASIL/metabolismo , Angiopatía Amiloide Cerebral/metabolismo , Enfermedades Arteriales Cerebrales/metabolismo , Circulación Cerebrovascular , Humanos , Enfermedades por Prión/metabolismoRESUMEN
In most organs of the body, immunological reactions involve the drainage of antigens and antigen presenting cells (APCs) along defined lymphatic channels to regional lymph nodes. The CNS is considered to be an immunologically privileged organ with no conventional lymphatics. However, immunological reactions do occur in the CNS in response to infections and in immune-mediated disorders such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Here, we review evidence that cervical lymph nodes play a role in B and T cell mediated immune reactions in the CNS. Then we define the separate pathways by which interstitial fluid (ISF) and CSF drain to cervical lymph nodes. ISF and solutes drain from the brain along the 100-150nm-wide basement membranes in the walls of capillaries and arteries. In humans, this perivascular pathway is outlined by the deposition of insoluble amyloid (Abeta) in capillary and artery walls in cerebral amyloid angiopathy in Alzheimer's disease. The failure of APCs to migrate to lymph nodes along perivascular lymphatic drainage pathways may be a major factor in immunological privilege of the brain. Lymphatic drainage of CSF is predominantly through the cribriform plate into nasal lymphatics. Lymphatic drainage of ISF and CSF and the specialised cervical lymph nodes to which they drain play significant roles in the induction of immunological tolerance and of adaptive immunological responses in the CNS. Understanding the afferent and efferent arms of the CNS lymphatic system will be valuable for the development of therapeutic strategies for diseases such as MS.
RESUMEN
The brain has no conventional lymphatics, but solutes injected into it drain along artery walls and reach lymph nodes in the neck. This study seeks to identify cervical lymph nodes related to the human internal carotid artery (ICA) that could act as the first regional lymph nodes for the brain. Bilateral dissections were carried out on four embalmed human heads, from the level of the carotid bifurcation in the neck, to the base of the skull. Lymph nodes from every specimen were processed for histological examination. A total of 51 deep cervical lymph nodes were identified: 12 lymph nodes (confirmed by histological examination) were observed to be in direct relationship with the ICA. These lymph nodes were found within the carotid sheath and had average diameters of 13.5 x 4.8 mm. Solutes and interstitial fluid from the brain may drain along the walls of cerebral arteries and reach these lymph nodes. They may be sites of stimulation of immune responses against antigens from the brain.
Asunto(s)
Arteria Carótida Interna/anatomía & histología , Ganglios Linfáticos/anatomía & histología , Base del Cráneo/anatomía & histología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , MasculinoAsunto(s)
Nervio Ciático/anomalías , Anciano , Artroplastia de Reemplazo de Cadera/métodos , Humanos , Masculino , Nervio Peroneo/anatomía & histología , Nervio Ciático/anatomía & histología , Neuropatía Ciática/etiología , Neuropatía Ciática/prevención & control , Nervio Tibial/anatomía & histologíaRESUMEN
UNLABELLED: Elimination of interstitial fluid and solutes plays a role in homeostasis in the brain, but the pathways are unclear. Previous work suggests that interstitial fluid drains along the walls of arteries. AIMS: to define the pathways within the walls of capillaries and arteries for drainage of fluid and solutes out of the brain. METHODS: Fluorescent soluble tracers, dextran (3 kDa) and ovalbumin (40 kDa), and particulate fluospheres (0.02 microm and 1.0 microm in diameter) were injected into the corpus striatum of mice. Brains were examined from 5 min to 7 days by immunocytochemistry and confocal microscopy. RESULTS: soluble tracers initially spread diffusely through brain parenchyma and then drain out of the brain along basement membranes of capillaries and arteries. Some tracer is takenf up by vascular smooth muscle cells and by perivascular macrophages. No perivascular drainage was observed when dextran was injected into mouse brains following cardiac arrest. Fluospheres expand perivascular spaces between vessel walls and surrounding brain, are ingested by perivascular macrophages but do not appear to leave the brain even following an inflammatory challenge with lipopolysaccharide or kainate. CONCLUSIONS: capillary and artery basement membranes act as 'lymphatics of the brain' for drainage of fluid and solutes; such drainage appears to require continued cardiac output as it ceases following cardiac arrest. This drainage pathway does not permit migration of cells from brain parenchyma to the periphery. Amyloid-beta is deposited in basement membrane drainage pathways in cerebral amyloid angiopathy, and may impede elimination of amyloid-beta and interstitial fluid from the brain in Alzheimer's disease. Soluble antigens, but not cells, drain from the brain by perivascular pathways. This atypical pattern of drainage may contribute to partial immune privilege of the brain and play a role in neuroimmunological diseases such as multiple sclerosis.