[Frontiers in Bioscience 17, 2024-2034, June 1, 2012]

Reviewing reasons for the decreased CSF Abeta42 concentration in Alzheimer disease

Petra E. Spies1, Marcel M. Verbeek2,3, Thomas van Groen4,5, Jurgen A.H.R. Claassen1

1Department of Geriatric Medicine, Radboud University Nijmegen Medical Center, Donders Institute for Brain, Cognition and Behaviour, and Alzheimer Center Nijmegen, Nijmegen, The Netherlands, 2Department of Neurology, Radboud University Nijmegen Medical Center, Donders Institute for Brain, Cognition and Behaviour, and Alzheimer Center Nijmegen, Nijmegen, The Netherlands, 3Department of Laboratory Medicine, Radboud University Nijmegen Medical Center, Donders Institute for Brain, Cognition and Behaviour, and Alzheimer Center Nijmegen, Nijmegen, The Netherlands, 4Department of Cell Biology, Center for Glial Biology, University of Alabama at Birmingham, Birmingham, USA, 5Department of Neurobiology, Center for Glial Biology, University of Alabama at Birmingham, Birmingham, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Abeta42 metabolism under normal conditions
3.1. Production of Abeta42
3.2. Degradation of Abeta42
3.2.1. Proteases
3.2.2. Microglia
3.3. Clearance of Abeta42
3.3.1. Active transport of Abeta from ISF to systemic circulation
3.3.2. Drainage of Abeta with ISF to lymphatics
3.3.3. Transport of Abeta from ISF to CSF
3.3.4. Absorption of Abeta from CSF to systemic circulation
3.3.5. Drainage of Abeta with CSF to lymphatics
4. Why is CSF Abeta42 decreased in Alzheimer disease?
4.1. Is Abeta42 production reduced?
4.2. Is Abeta42 degradation increased?
4.3. Is microglial uptake of Abeta42 increased?
4.4. Is Abeta42 clearance affected?
4.4.1. Is clearance of Abeta42 from ISF increased?
4.4.2. Is transport of Abeta42 from ISF to CSF hampered?
4.4.2.1.Hampered flow of ISF to CSF
4.4.2.2.Perivascular deposition of Abeta
4.4.2.3.Parenchymal aggregation of Abeta
4.4.3. Is CSF Abeta42 decreased because more Abeta42 is cleared from CSF?
5. Perspective
6. Acknowledgements
7. References

1. ABSTRACT

Cerebrospinal fluid (CSF) amyloid beta42 (Abeta42) concentrations are decreased in patients with Alzheimer disease (AD). Consequently, low Abeta42 is considered a positive biomarker for AD. Surprisingly, the mechanisms that underlie the decrease in CSF Abeta42 remain speculative. Better understanding of this biomarker is an essential step to unravel AD pathophysiology and to develop and evaluate treatment. Therefore, we systematically examined the possible reasons for the decreased CSF Abeta42 concentration in AD. Under normal conditions, Abeta42 can be degraded by proteases, taken up by microglia, or cleared from the brain interstitial fluid across the blood brain barrier. Alternatively, it can be transported to the CSF and be cleared from there. Aggregation of Abeta42 appears the most likely cause for the decreased CSF Abeta42 concentration in AD: the aggregated state inhibits Abeta42 from being transported from the ISF to the CSF. Evidence for other possibilities such as a decreased production of Abeta42, an increased proteolytic breakdown or microglial uptake of Abeta42, or an increased clearance of Abeta42 to the blood, is - at best - scarce or even absent.