title: Diurnal patterns of soluble amyloid precursor protein metabolites in the human central nervous system.
abstract: The amyloid-β (Aβ) protein is diurnally regulated in both the cerebrospinal fluid and blood in healthy adults; circadian amplitudes decrease with aging and the presence of cerebral Aβ deposits. The cause of the Aβ diurnal pattern is poorly understood. One hypothesis is that the Amyloid Precursor Protein (APP) is diurnally regulated, leading to APP product diurnal patterns. APP in the central nervous system is processed either via the β-pathway (amyloidogenic), generating soluble APP-β (sAPPβ) and Aβ, or the α-pathway (non-amyloidogenic), releasing soluble APP-α (sAPPα). To elucidate the potential contributions of APP to the Aβ diurnal pattern and the balance of the α- and β- pathways in APP processing, we measured APP proteolytic products over 36 hours in human cerebrospinal fluid from cognitively normal and Alzheimer's disease participants. We found diurnal patterns in sAPPα, sAPPβ, Aβ40, and Aβ42, which diminish with increased age, that support the hypothesis that APP is diurnally regulated in the human central nervous system and thus results in Aβ diurnal patterns. We also found that the four APP metabolites were positively correlated in all participants without cerebral Aβ deposits. This positive correlation suggests that the α- and β- APP pathways are non-competitive under normal physiologic conditions where APP availability may be the limiting factor that determines sAPPα and sAPPβ production. However, in participants with cerebral Aβ deposits, there was no correlation of Aβ to sAPP metabolites, suggesting that normal physiologic regulation of cerebrospinal fluid Aβ is impaired in the presence of amyloidosis. Lastly, we found that the ratio of sAPPβ to sAPPα was significantly higher in participants with cerebral Aβ deposits versus those without deposits. Therefore, the sAPPβ to sAPPα ratio may be a useful biomarker for cerebral amyloidosis.
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Justyna A
authors.initials: JA
authors.lastname: Dobrowolska
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Tom
authors.initials: T
authors.lastname: Kasten
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Tammie L S
authors.initials: TL
authors.lastname: Benzinger
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Wendy
authors.initials: W
authors.lastname: Sigurdson
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Vitaliy
authors.initials: V
authors.lastname: Ovod
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.affiliation: Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America; Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, United States of America; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Bateman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid*; D016022:Case-Control Studies; D002490:Central Nervous System / Q000378:metabolism* / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000134:cerebrospinal fluid* / Q000473:pathology; D002940:Circadian Rhythm; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C000593264:amyloid beta-protein (10-40); C538897:amyloid beta-protein (40-42)