Apolipoprotein E4 and meningeal lymphatics in Alzheimer disease: a conceptual framework
Datum
2021Language
en
Schlagwort
Zusammenfassung
The potential existence and roles of the meningeal lymphatic system in normal and pathological brain function have been a long-standing enigma. Recent evidence suggests that meningeal lymphatic vessels are present in both the mouse and human brain; in mice, they seem to play a role in clearing toxic amyloid-beta peptides, which have been connected with Alzheimer disease (AD). Here, we review the evidence linking the meningeal lymphatic system with human AD. Novel findings suggest that the recently described meningeal lymphatic vessels could be linked to, and possibly drain, the efferent paravascular glial lymphatic (glymphatic) system carrying cerebrospinal fluid, after solute and immune cell exchange with brain interstitial fluid. In so doing, the glymphatic system could contribute to the export of toxic solutes and immune cells from the brain (an exported fluid we wish to describe as glymph, similarly to lymph) to the meningeal lymphatic system; the latter, by being connected with downstream anatomic regions, carries the glymph to the conventional cervical lymphatic vessels and nodes. Thus, abnormal function in the meningeal lymphatic system could, in theory, lead to the accumulation, in the brain, of amyloid-beta, cellular debris, and inflammatory mediators, as well as immune cells, resulting in damage of the brain parenchyma and, in turn, cognitive and other neurologic dysfunctions. In addition, we provide novel insights into APOE4—the leading genetic risk factor for AD—and its relation to the meningeal lymphatic system. In this regard, we have reanalyzed previously published RNA-Seq data to show that induced pluripotent stem cells (iPSCs) carrying the APOE4 allele (either as APOE4 knock-in or stemming from APOE4 patients) express lower levels of (a) genes associated with lymphatic markers, and (b) genes for which well-characterized missense mutations have been linked to peripheral lymphedema. Taking into account this evidence, we propose a new conceptual framework, according to which APOE4 could play a novel role in the premature shrinkage of meningeal lymphatic vessels (meningeal lymphosclerosis), leading to abnormal meningeal lymphatic functions (meningeal lymphedema), and, in turn, reduction in the clearance of amyloid-beta and other macromolecules and inflammatory mediators, as well as immune cells, from the brain, exacerbation of AD manifestations, and progression of the disease. Altogether, these findings and their potential interpretations may herald novel diagnostic tools and therapeutic approaches in patients with AD. © 2020, The Author(s).
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Global, regional, and national age-sex specifc mortality for 264 causes of death, 1980-2016: A systematic analysis for the Global Burden of Disease Study 2016
Naghavi M., Abajobir A.A., Abbafati C., Abbas K.M., Abd-Allah F., Abera S.F., Aboyans V., Adetokunboh O., Ärnlöv J., Afshin A., Agrawal A., Kiadaliri A.A., Ahmadi A., Ahmed M.B., Aichour A.N., Aichour I., Aichour M.T.E., Aiyar S., Al-Eyadhy A., Alahdab F., Al-Aly Z., Alam K., Alam N., Alam T., Alene K.A., Ali S.D., Alizadeh-Navaei R., Alkaabi J.M., Alkerwi A., Alla F., Allebeck P., Allen C., Al-Raddadi R., Alsharif U., Altirkawi K.A., Alvis-Guzman N., Amare A.T., Amini E., Ammar W., Amoako Y.A., Anber N., Andersen H.H., Andrei C.L., Androudi S., Ansari H., Antonio C.A.T., Anwari P., Arora M., Artaman A., Aryal K.K., Asayesh H., Asgedom S.W., Atey T.M., Avila-Burgos L., Avokpaho E.F.G.A., Awasthi A., Quintanilla B.P.A., Béjot Y., Babalola T.K., Bacha U., Balakrishnan K., Barac A., Barboza M.A., Barker-Collo S.L., Barquera S., Barregard L., Barrero L.H., Baune B.T., Bedi N., Beghi E., Bekele B.B., Bell M.L., Bennett J.R., Bensenor I.M., Berhane A., Bernabé E., Betsu B.D., Beuran M., Bhatt S., Biadgilign S., Bienhof K., Bikbov B., Bisanzio D., Bourne R.R.A., Breitborde N.J.K., Bulto L.N.B., Bumgarner B.R., Butt Z.A., Cárdenas R., Cahuana-Hurtado L., Cameron E., Campuzano J.C., Car J., Carrero J.J., Carter A., Casey D.C., Castañeda-Orjuela C.A., Catalá-López F., Charlson F.J., Chibueze C.E., Chimed-Ochir O., Chisumpa V.H., Chitheer A.A., Christopher D.J., Ciobanu L.G., Cirillo M., Cohen A.J., Colombara D., Cooper C., Cowie B.C., Criqui M.H., Dandona L., Dandona R., Dargan P.I., Das Neves J., Davitoiu D.V., Davletov K., De Courten B., Degenhardt L., Deiparine S., Deribe K., Deribew A., Dey S., Dicker D., Ding E.L., Djalalinia S., Do H.P., Doku D.T., Douwes-Schultz D., Driscoll T.R., Dubey M., Duncan B.B., Echko M., El-Khatib Z.Z., Ellingsen C.L., Enayati A., Erskine H.E., Eskandarieh S., Esteghamati A., Ermakov S.P., Estep K., Sa Farinha C.S., Faro A., Farzadfar F., Feigin V.L., Fereshtehnejad S.-M., Fernandes J.C., Ferrari A.J., Feyissa T.R., Filip I., Finegold S., 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Thrift A.G., Tobe-Gai R., Topor-Madry R., Torre A., Tortajada M., Towbin J.A., Tran B.X., Troeger C., Truelsen T., Tsoi D., Tuzcu E.M., Tyrovolas S., Ukwaja K.N., Undurraga E.A., Updike R., Uthman O.A., Uzochukwu B.S.C., Van Boven J.F.M., Vasankari T., Venketasubramanian N., Violante F.S., Vlassov V.V., Vollset S.E., Vos T., Wakayo T., Wallin M.T., Wang Y.-P., Weiderpass E., Weintraub R.G., Weiss D.J., Werdecker A., Westerman R., Whetter B., Whiteford H.A., Wijeratne T., Wiysonge C.S., Woldeyes B.G., Wolfe C.D.A., Woodbrook R., Workicho A., Xavier D., Xiao Q., Xu G., Yaghoubi M., Yakob B., Yano Y., Yaseri M., Yimam H.H., Yonemoto N., Yoon S.-J., Yotebieng M., Younis M.Z., Zaidi Z., El Sayed Zaki M., Zegeye E.A., Zenebe Z.M., Zerfu T.A., Zhang A.L., Zhang X., Zipkin B., Zodpey S., Lopez A.D., Murray C.J.L., GBD 2016 Causes of Death Collaborators (2017)Background: Monitoring levels and trends in premature mortality is crucial to understanding how societies can address prominent sources 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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
de Rojas I., Moreno-Grau S., Tesi N., Grenier-Boley B., Andrade V., Jansen I.E., Pedersen N.L., Stringa N., Zettergren A., Hernández I., Montrreal L., Antúnez C., Antonell A., Tankard R.M., Bis J.C., Sims R., Bellenguez C., Quintela I., González-Perez A., Calero M., Franco-Macías E., Macías J., Blesa R., Cervera-Carles L., Menéndez-González M., Frank-García A., Royo J.L., Moreno F., Huerto Vilas R., Baquero M., Diez-Fairen M., Lage C., García-Madrona S., García-González P., Alarcón-Martín E., Valero S., Sotolongo-Grau O., Ullgren A., Naj A.C., Lemstra A.W., Benaque A., Pérez-Cordón A., Benussi A., Rábano A., Padovani A., Squassina A., de Mendonça A., Arias Pastor A., Kok A.A.L., Meggy A., Pastor A.B., Espinosa A., Corma-Gómez A., Martín Montes A., Sanabria Á., DeStefano A.L., Schneider A., Haapasalo A., Kinhult Ståhlbom A., Tybjærg-Hansen A., Hartmann A.M., Spottke A., Corbatón-Anchuelo A., Rongve A., Borroni B., Arosio B., Nacmias B., Nordestgaard B.G., Kunkle B.W., Charbonnier C., 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Vandenberghe R., Cecchetti R., Ghidoni R., Frikke-Schmidt R., Sorbi S., Hägg S., Engelborghs S., Helisalmi S., Botne Sando S., Kern S., Archetti S., Boschi S., Fostinelli S., Gil S., Mendoza S., Mead S., Ciccone S., Djurovic S., Heilmann-Heimbach S., Riedel-Heller S., Kuulasmaa T., del Ser T., Lebouvier T., Polak T., Ngandu T., Grimmer T., Bessi V., Escott-Price V., Giedraitis V., Deramecourt V., Maier W., Jian X., Pijnenburg Y.A.L., Smith A.D., Saenz A., Bizzarro A., Lauria A., Vacca A., Solomon A., Anastasiou A., Richardson A., Boland A., Koivisto A., Daniele A., Greco A., Marianthi A., McGuinness B., Fin B., Ferrari C., Custodero C., Ferrarese C., Ingino C., Mangone C., Reyes Toso C., Martínez C., Cuesta C., Muchnik C., Joachim C., Ortiz C., Besse C., Johansson C., Zoia C.P., Laske C., Anastasiou C., Palacio D.L., Politis D.G., Janowitz D., Craig D., Mann D.M., Neary D., Jürgen D., Daian D., Belezhanska D., Kohler E., Castaño E.M., Koutsouraki E., Chipi E., De Roeck E., Costantini 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Sevillano Z., Abdelnour C., Aguilera N., Alarcon E., Alegret M., Benaque A., Boada M., Buendia M., Cañabate P., Carracedo A., Corbatón-Anchuelo A., Diego S., Espinosa A., Gailhajenet A., Gil S., Guitart M., Hernández I., Ibarria M., Lafuente A., Macias J., Maroñas O., Martín E., Martínez M.T., Marquié M., Mauleón A., Montrreal L., Moreno-Grau S., Moreno M., Orellana A., Ortega G., Pancho A., Pelejá E., Pérez-Cordon A., Preckler S., Quintela I., Real L.M., Rosende-Roca M., Ruiz A., Sáez M.E., Sanabria A., Serrano-Rios M., Sotolongo-Grau O., Tárraga L., Valero S., Vargas L., Adarmes-Gómez A.D., Alarcón-Martín E., Alonso M.D., Álvarez I., Álvarez V., Amer-Ferrer G., Antequera M., Antúnez C., Baquero M., Bernal M., Blesa R., Boada M., Buiza-Rueda D., Bullido M.J., Burguera J.A., Calero M., Carrillo F., Carrión-Claro M., Casajeros M.J., Clarimón J., Cruz-Gamero J.M., de Pancorbo M.M., del Ser T., Diez-Fairen M., Escuela R., Garrote-Espina L., Fortea J., Franco-Macías E., Frank-García A., 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P., Lopez de Munain A., García-Alberca J.M., Bullido M.J., Álvarez V., Real L.M., Scheltens P., Holstege H., Marquié M., Sáez M.E., Amouyel P., Schellenberg G.D., Williams J., Seshadri S., van Duijn C.M., Mather K.A., Sánchez-Valle R., Serrano-Ríos M., Orellana A., Tárraga L., Blennow K., Huisman M., Andreassen O.A., Posthuma D., Clarimón J., Boada M., van der Flier W.M., Ramirez A., Lambert J.-C., van der Lee S.J., Ruiz A., EADB contributors, The GR@ACE study group, DEGESCO consortium, IGAP (ADGC, CHARGE, EADI, GERAD), PGC-ALZ consortia (2021)Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical ... -
Yellow nail syndrome or diffuse lymphatic network disease
Christu, K. A.; Pastaka, C.; Papadopoulos, D.; Klimi, E.; Gourgoulianis, K. I. (2002)We report a man aged 68 years old with pneumothorax and chronic bilateral pleural effusion in association with a history of yellow nails. The diagnosis of yellow nail syndrome based on yellow nails, lymphedema, chronic ...