BACKGROUND: Individuals with Down's syndrome (DS) develop early Alzheimer's disease (AD) with β-amyloid (Aβ) plaque pathology. The extra amyloid precursor protein (APP) gene copy in DS is believed to result in a 50% increase in Aβ production, but it is unclear how this relates to the development of other AD hallmarks, including axonal degeneration and microglia cell activation, and to other neurological problems in DS, including disturbed sleep regulation. OBJECTIVE: To evaluate if cerebrospinal fluid (CSF) biomarkers for cerebral amyloidosis, axonal degeneration, microglial activation and sleep regulation were altered in young and old patients with DS, and if these biomarkers were related to altered Aβ and APP metabolism, reflected by CSF levels of different Aβ and APP peptides. METHODS: CSF from DS patients (n=12) and healthy controls (n=20) were analyzed for Aβ peptides (Aβ1-42, AβX-38/40/42), secreted APP species (sAPPα/β), biomarkers for AD-like axonal degeneration [total tau (T-tau), phosphorylated tau], microglial activation (YKL-40, CC chemokine ligand 2) and orexin-A, which is a peptide involved in sleep regulation. We compared biomarker levels between groups and tested for relations between biomarkers, disease stage and age. RESULTS: Several of the markers were specifically increased in DS, including AβX-40, sAPPα and sAPPβ. Οrexin-A was significantly decreased in DS and correlated with Aβ and sAPP. Orexin-A decreased with age in DS, while T-tau and YKL-40 increased with age. CONCLUSION: Down's patients have increased APP and Aβ production and increased microglial activation with age. The orexin-A metabolism is disturbed in DS and may be linked to APP and Aβ production. Biomarker studies of DS may contribute to our understanding of the amyloidogenic and neurodegenerative process in AD.
BACKGROUND: Individuals with Down's syndrome (DS) develop early Alzheimer's disease (AD) with β-amyloid (Aβ) plaque pathology. The extra amyloid precursor protein (APP) gene copy in DS is believed to result in a 50% increase in Aβ production, but it is unclear how this relates to the development of other AD hallmarks, including axonal degeneration and microglia cell activation, and to other neurological problems in DS, including disturbed sleep regulation. OBJECTIVE: To evaluate if cerebrospinal fluid (CSF) biomarkers for cerebral amyloidosis, axonal degeneration, microglial activation and sleep regulation were altered in young and old patients with DS, and if these biomarkers were related to altered Aβ and APP metabolism, reflected by CSF levels of different Aβ and APP peptides. METHODS: CSF from DS patients (n=12) and healthy controls (n=20) were analyzed for Aβ peptides (Aβ1-42, AβX-38/40/42), secreted APP species (sAPPα/β), biomarkers for AD-like axonal degeneration [total tau (T-tau), phosphorylated tau], microglial activation (YKL-40, CC chemokine ligand 2) and orexin-A, which is a peptide involved in sleep regulation. We compared biomarker levels between groups and tested for relations between biomarkers, disease stage and age. RESULTS: Several of the markers were specifically increased in DS, including AβX-40, sAPPα and sAPPβ. Οrexin-A was significantly decreased in DS and correlated with Aβ and sAPP. Orexin-A decreased with age in DS, while T-tau and YKL-40 increased with age. CONCLUSION: Down's patients have increased APP and Aβ production and increased microglial activation with age. The orexin-A metabolism is disturbed in DS and may be linked to APP and Aβ production. Biomarker studies of DS may contribute to our understanding of the amyloidogenic and neurodegenerative process in AD.
Authors: Ricardo S Osorio; Emma L Ducca; Margaret E Wohlleber; Emily B Tanzi; Tyler Gumb; Akosua Twumasi; Samuel Tweardy; Clifton Lewis; Esther Fischer; Viachaslau Koushyk; Maria Cuartero-Toledo; Mohammed O Sheikh; Elizabeth Pirraglia; Henrik Zetterberg; Kaj Blennow; Shou-En Lu; Lisa Mosconi; Lidia Glodzik; Sonja Schuetz; Andrew W Varga; Indu Ayappa; David M Rapoport; Mony J de Leon Journal: Sleep Date: 2016-06-01 Impact factor: 5.849
Authors: Erik Portelius; Mikko Hölttä; Hilkka Soininen; Maria Bjerke; Henrik Zetterberg; Anni Westerlund; Sanna-Kaisa Herukka; Kaj Blennow; Niklas Mattsson Journal: Neuromolecular Med Date: 2014-04-18 Impact factor: 3.843
Authors: Anne M Fagan; Rachel L Henson; Yan Li; Anna H Boerwinkle; Chengjie Xiong; Randall J Bateman; Alison Goate; Beau M Ances; Eric Doran; Bradley T Christian; Florence Lai; H Diana Rosas; Nicole Schupf; Sharon Krinsky-McHale; Wayne Silverman; Joseph H Lee; William E Klunk; Benjamin L Handen; Ricardo F Allegri; Jasmeer P Chhatwal; Gregory S Day; Neill R Graff-Radford; Mathias Jucker; Johannes Levin; Ralph N Martins; Colin L Masters; Hiroshi Mori; Catherine J Mummery; Yoshiki Niimi; John M Ringman; Stephen Salloway; Peter R Schofield; Mikio Shoji; Ira T Lott Journal: Lancet Neurol Date: 2021-08 Impact factor: 59.935
Authors: Jonathan Cedernaes; Ricardo S Osorio; Andrew W Varga; Korey Kam; Helgi B Schiöth; Christian Benedict Journal: Sleep Med Rev Date: 2016-02-11 Impact factor: 11.609
Authors: Linda Schauenburg; Filip Liebsch; Murat Eravci; Magnus C Mayer; Christoph Weise; Gerhard Multhaup Journal: Sci Rep Date: 2018-01-30 Impact factor: 4.379