Reviewing reasons for the decreased CSF Abeta42 concentration in Alzheimer disease.
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.
Department of Geriatric Medicine, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. PetraESpies@gmail.com
Petra E
PE
Spies
Marcel M
MM
Verbeek
Thomas
T
van Groen
Jurgen A H R
JA
Claassen
D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid* / Q000737:chemistry; D000818:Animals; D001693:Biological Transport, Active; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism; D006801:Humans; D008196:Lymph / Q000378:metabolism; D017628:Microglia / Q000378:metabolism; D008959:Models, Neurological; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid* / Q000737:chemistry; D010447:Peptide Hydrolases / Q000378:metabolism; D055503:Protein Multimerization
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D010447:Peptide Hydrolases