期刊
BRAIN
卷 139, 期 -, 页码 174-192出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awv318
关键词
Alzheimer's disease; apolipoprotein E; beta-amyloid; astrocyte neurodegeneration; inflammation
资金
- Loo and Hans Osterman Foundation
- KI Foundations
- Olle Engkvist Byggmastare Foundation
- Ake Wibergs Foundation
- Ahlen-Foundation
- Gunvor and Josef Aners Foundation
- Magnus Bergvalls Foundation
- Demens Foundation (Demensfonden)
- Gun and Bertil Stohnes Foundation
- Ragnhild and Einar Lundstroms Foundation
- Foundation for Sigurd and Elsa Goljes Memory
- Tore Nilsson Foundation
- Foundation for Old Servants
- Swedish Research Council [05817]
- Karolinska Institutet Strategic Neuroscience programme
- Stockholm County Council-Karolinska Institutet
- Swedish Brain Power
- Swedish Brain Foundation
- Alzheimer Foundation in Sweden
- EU FP7 large scale integrating project INMiND
Amyloid-beta peptides, through highly sophisticated enzymatic machinery, are universally produced and released in an action potential synchronized manner into the interstitial fluids in the brain. Yet no native functions are attributed to amyloid-beta. The amyloid-beta hypothesis ascribes just neurotoxicity properties through build-up of soluble homomeric amyloid-beta oligomers or fibrillar deposits. Apolipoprotein-epsilon 4 ( APOE4) allele is the only confirmed genetic risk factor of sporadic Alzheimer's disease; once more it is unclear how it increases the risk of Alzheimer's disease. Similarly, central cholinergic signalling is affected selectively and early in the Alzheimer's disease brain, again why cholinergic neurons show this sensitivity is still unclear. However, the three main known Alzheimer's disease risk factors, advancing age, female gender and APOE4, have been linked to a high apolipoprotein-E and accumulation of the acetylcholine degrading enzyme, butyrylcholinesterase in cerebrospinal fluids of patients. Furthermore, numerous reports indicate that amyloid-beta interacts with butyrylcholinesterase and apolipoprotein-E. We have proposed that this interaction leads to formation of soluble ultrareactive acetylcholine-hydrolyzing complexes termed BAbACs, to adjust at demand both synaptic and extracellular acetylcholine signalling. This hypothesis predicted presence of acetylcholine-synthesizing enzyme, choline acetyltransferase in extracellular fluids to allow maintenance of equilibrium between breakdown and synthesis of acetylcholine through continuous in situ syntheses. A recent proof-of-concept study led to the discovery of this enzyme in the human extracellular fluids. We report here that apolipoprotein-E, in particular e4 isoprotein acts as one of the strongest endogenous anti-amyloid-beta fibrillization agents reported in the literature. At biological concentrations, apolipoprotein-E prevented amyloid-beta fibrillization for at least 65 h. We show that amyloid-beta interacts readily in an apolipoprotein-facilitated manner with butyrylcholinesterase, forming highly stable and soluble complexes, BAbACs, which can be separated in their native states by sucrose density gradient technique. Enzymological analyses further evinced that amyloid-beta concentration dependently increased the acetylcholine-hydrolyzing capacity of cholinesterases. In silico biomolecular analysis further deciphered the allosteric amino acid fingerprint of the amyloid-beta-cholinesterase molecular interaction in formation of BAbACs. In the case of butyrylcholinesterase, the results indicated that amyloid-beta interacts with a putative activation site at the mouth of its catalytic tunnel, most likely leading to increased acetylcholine influx into the catalytic site, and thereby increasing the intrinsic catalytic rate of butyrylcholinesterase. In conclusion, at least one of the native physiological functions of amyloid-beta is allosteric modulation of the intrinsic catalytic efficiency of cholinesterases, and thereby regulation of synaptic and extrasynaptic cholinergic signalling. High apolipoprotein-E may pathologically alter the biodynamics of this amyloid-beta function.
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