TY - JOUR
T1 - Diurnal patterns of soluble amyloid precursor protein metabolites in the human central nervous system
AU - Dobrowolska, Justyna A.
AU - Kasten, Tom
AU - Huang, Yafei
AU - Benzinger, Tammie L.S.
AU - Sigurdson, Wendy
AU - Ovod, Vitaliy
AU - Morris, John C.
AU - Bateman, Randall J.
N1 - Funding Information:
The authors have read the journal's policy and have the following potential or perceived conflicts: Eli Lilly provided antibodies for this study. Neither RJB, nor his family, owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical company. He receives research support from the Alzheimer's Association, an anonymous foundation, and Merck research collaboration, and is funded by NIH grants # R01NS065667, U17AG032438, U01AG042791, and P50AG005681. RJB is currently Director of the Dominantly Inherited Alzheimer's Network (DIAN) Trials Unit which has underway an antidementia drug clinical trial in collaboration with Eli Lilly and Roche. RJB heads the DIAN Pharma Consortium (AIP, Biogen Idec, Elan, Eisai, EnVivo, Genentech, Eli Lilly, Novartis, Pfizer, Roche, Sanofi-Aventis). He receives research support from both the DIAN Pharma Consortium and from Eli Lilly and Roche for the current clinical trial. In 2007, RJB co-founded the biotechnology company C2N Diagnostics and serves as one of its scientific advisors. In the past, RJB has participated in a clinical trial of an antidementia drug sponsored by Eli Lilly and has served as a consultant for the following companies: Pfizer, DZNE, Probiodrug AG, Medscape, En Vivo (SAB). He has also been an invited speaker at: Bristol-Myers Squibb, Eli Lilly, Merck, Pfizer, Elan, Wyeth, Novartis, Abbott, Biogen Idec, Roche and Takeda Foundation. RJB is co-inventor on U.S. patent 7,892,845: “Methods for measuring the metabolism of neurally derived biomolecules in vivo,” Washington University, with RJB and JAD as co-inventors, has also submitted the U.S. non-provisional patent application “Methods for measuring the metabolism of CNS derived biomolecules in vivo,” serial #12/267,974. RJB is also co-inventor on U.S. Provisional Application 61/728,692: “Methods of Diagnosing Amyloid Pathologies Using Analysis of Amyloid-Beta Enrichment Kinetics.” Neither JCM, nor his family, owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. JCM has participated or is currently participating in clinical trials of antidementia drugs sponsored by the following companies: Janssen Immunotherapy and Pfizer. JCM has served as a consultant for Lilly USA. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by NIH grants # P50AG005681, P01AG003991, P01AG026276 and U19AG032438. TLSB served on an advisory board for Eli Lilly in 2011; and, for projects unrelated to the study presented herein, has research funding from Avid Radiopharmaceuticals. The remaining co-authors (TK, YH, VO, and WS) have declared that no competing interests exist. Please note that the potential or perceived conflicts disclosed in the Competing Interests section do not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
PY - 2014/3/19
Y1 - 2014/3/19
N2 - 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<1inf>, 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.
AB - 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<1inf>, 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.
UR - http://www.scopus.com/inward/record.url?scp=84898612024&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0089998
DO - 10.1371/journal.pone.0089998
M3 - Article
C2 - 24646516
AN - SCOPUS:84898612024
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 3
M1 - e89998
ER -