Alzheimer's disease (AD) is the most common cause of dementia and currently has no disease modifying treatments or simple accurate diagnostic tests. Several targets have been identified as contributors to AD pathophysiology (e.g. A?, tau, inflammation), with most current therapeutic approaches targeting amyloid- beta (A?). However, A? pathophysiology is not fully understood. The amyloid hypothesis proposes that amyloid-beta over-production or under-clearance leads to a common pathophysiology resulting in a cascade of events which culminate in neuronal death and manifest as progressive clinical dementia of the Alzheimer's type. Therefore, treatment of AD during the mild to moderate stage of dementia in therapeutic trials may be too late as 50% of AD specific neurons are already dead. Thus, a better understanding of the pathophysiology of A? and biomarkers based on A? pathophysiology are necessary to offer anti-A? therapeutic strategies their best chance of success. The overall goal of this project is to determine the changes that occur in A? metabolism in AD and model the production, transport, metabolism and clearance of A? in the human central nervous system (CNS) and periphery to improve clinical trial designs. In order to understand A? kinetics in the pathophysiology of AD, the applicant will use Stable Isotope Labeling Kinetics (SILK) to metabolically label and quantify proteins in the human CNS.
The specific aims are 1) to determine A? isoform production and clearance rates in steady state infusion labeled blood, and 2) to measure blood and CSF A? SILK from a pulse oral labeled SILK protocol in AD and control participants. In SA1, blood A? kinetics will be compared to CSF A? kinetics and combined utilizing multi-compartment and structural models to determine the direction and magnitude of transport and breakdown. The oral labeling protocol in SA2 will provide additional information on A? kinetics and potentially better distinguish AD from controls. Results from SA2 will be incorporated into complimentary models with results from SA1 and ongoing studies to provide measures of A? production, transport, and breakdown within and between the brain, CSF and blood compartments. The proposed work builds on the prior pioneering approach that has influenced the understanding of A?'s role in the amyloid hypothesis and pathophysiological causes of AD. The approach has been extended with significantly improved techniques, novel labeling protocols, and cutting-edge modeling approaches. In summary, these studies will provide the first human measurements of A? kinetics in blood, develop comprehensive models of A? metabolism, and determine changes of A? metabolism in AD that will lead to better clinical trial designs and potentially a blood biomarker for AD.

Public Health Relevance

Alzheimer's disease (AD) is the most common cause of dementia and currently has no disease modifying treatments or simple accurate diagnostic tests. The goal of this project is to study how amyloid-beta (a protein thought to cause AD) is made, transported and cleared in the human body. Findings from this study may lead to better treatments for AD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroscience and Neurodegeneration Study Section (CNN)
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Corriveau, Roderick A
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Washington University
Schools of Medicine
Saint Louis
United States
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Lucey, Brendan P; Mawuenyega, Kwasi G; Patterson, Bruce W et al. (2016) Associations Between β-Amyloid Kinetics and the β-Amyloid Diurnal Pattern in the Central Nervous System. JAMA Neurol :
Elbert, Donald L; Patterson, Bruce W; Bateman, Randall J (2015) Analysis of a compartmental model of amyloid beta production, irreversible loss and exchange in humans. Math Biosci 261:48-61
Lucey, Brendan P; Gonzales, Celedon; Das, Ujjwas et al. (2015) An integrated multi-study analysis of intra-subject variability in cerebrospinal fluid amyloid-β concentrations collected by lumbar puncture and indwelling lumbar catheter. Alzheimers Res Ther 7:53
Patterson, Bruce W; Elbert, Donald L; Mawuenyega, Kwasi G et al. (2015) Age and amyloid effects on human central nervous system amyloid-beta kinetics. Ann Neurol 78:439-53
Crisp, Matthew J; Mawuenyega, Kwasi G; Patterson, Bruce W et al. (2015) In vivo kinetic approach reveals slow SOD1 turnover in the CNS. J Clin Invest 125:2772-80
Roberts, Kaleigh Filisa; Elbert, Donald L; Kasten, Tom P et al. (2014) Amyloid-β efflux from the central nervous system into the plasma. Ann Neurol 76:837-44
Wardlaw, Sharon L; Burant, Charles F; Klein, Samuel et al. (2014) Continuous 24-hour leptin, proopiomelanocortin, and amino acid measurements in human cerebrospinal fluid: correlations with plasma leptin, soluble leptin receptor, and amino acid levels. J Clin Endocrinol Metab 99:2540-8
Dobrowolska, Justyna A; Kasten, Tom; Huang, Yafei et al. (2014) Diurnal patterns of soluble amyloid precursor protein metabolites in the human central nervous system. PLoS One 9:e89998
Dobrowolska, Justyna A; Michener, Maria S; Wu, Guoxin et al. (2014) CNS amyloid-β, soluble APP-α and -β kinetics during BACE inhibition. J Neurosci 34:8336-46
Mawuenyega, Kwasi G; Kasten, Tom; Sigurdson, Wendy et al. (2013) Amyloid-beta isoform metabolism quantitation by stable isotope-labeled kinetics. Anal Biochem 440:56-62

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