Differential levels of apolipoprotein E and butyrylcholinesterase show strong association with pathological signs of Alzheimer's disease in the brain in vivo
2011 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 32, no 12, 2320.e15-2320.e32 p.Article in journal (Refereed) Published
Recently, we reported that 3 of the known risk factors of Alzheimer's disease (AD), i.e., advanced age, apolipoprotein E (ApoE) ε4, and female gender, are associated with differential levels of ApoE proteins and butyrylcholinesterase (BuChE) in the cerebrospinal fluid (CSF) of AD patients. The ApoE ε4 allele and certain BuChE polymorphisms synergistically affect the conversion rate of mild cognitive impairment (MCI) to AD. Here, we investigated interrelationships between ApoE and BuChE levels, and pathological markers of AD in vivo. CSF from patients with probable AD, assessed for cerebral glucose metabolism (CMRglc; n = 50) and Pittsburgh compound B (PIB) retention (β-amyloid [Aβ] load, n = 29) by positron emission tomography (PET), was used for measurement of BuChE, ApoE, Aβ, tau, phosphorylated tau (P-tau) and interleukin-1β (IL-1β) levels. Levels of ApoE and BuChE strongly correlated with CMRglc (fluorodeoxyglucose [FDG]-PET, r = 0.54, p < 0.0001, n = 50), cerebral Aβ load (PIB retention, r = 0.73, p < 0.0001, n = 29), and CSF P-tau (r = 0.73, p < 0.0001, n = 33). High ApoE protein was tied to low CMRglc and high PIB retention and P-tau. BuChE levels had opposite relationships. Other CSF covariates were levels of interleukin-1β and Aβ42peptide. The pattern of the patients' cognitive Z-scores strongly supported these observations. High ApoE protein was also linked to changes in 3 of the biodynamic properties of BuChE. In vitro analysis indicated that high ApoE protein levels were related to an increased pool of dormant BuChE molecules with an abnormally high intrinsic catalytic rate in CSF, which was “turned on” by excess Aβ peptides. The findings suggest that abnormally high levels of ApoE may play a causative role in the pathological events of AD, particularly those involving the early cholinergic deficit in the AD brain, through modulation of cholinesterases activities, hence disturbing the acetylcholine-dependent activity of neurons and nonexcitable cells such as glial cells.
Place, publisher, year, edition, pages
Elsevier, 2011. Vol. 32, no 12, 2320.e15-2320.e32 p.
apolipoprotein E, butyrylcholinesterase, Alzheimer’s disease, brain
Psychology Neurosciences Geriatrics
Research subject Psychology
IdentifiersURN: urn:nbn:se:su:diva-70445DOI: 10.1016/j.neurobiolaging.2010.04.028ISI: 000296379900035PubMedID: 20538374OAI: oai:DiVA.org:su-70445DiVA: diva2:481308
This research was supported by The Swedish Medical Research Council (project no. 05817), the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and the Karolinska Institute, and the following: Karolinska Institute Foundations; The Loo and Hans Osterman Foundation; The Old Servants Foundation; The Alzheimer Foundation, Sweden; Brainsfoundation; The Gun and Bertil Stohnes Foundation; The Magnus Bergvalls Foundation, Swedish Brain Power; DiMI; LSHB-CT-2005-512146 and The Foundation for Ragnhild and Einar Lundströms Memory. TD-S has received postdoctoral fellowships from “Riksföreningen för Åldrandeforskning” (National Society for Aging Research), and “Alzheimer Foundation, Sweden”.2012-01-202012-01-202012-02-01Bibliographically approved