Amyloid Peptide Aβ1‐42 Binds Selectively and with Picomolar Affinity to α7 Nicotinic Acetylcholine Receptors

Journal of Neurochemistry - Tập 75 Số 3 - Trang 1155-1161 - 2000
Hoau‐Yan Wang1, Daniel H. S. Lee1, Coralie B. Davis1, Richard P. Shank1
1R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, U.S.A.

Tóm tắt

Abstract: We have recently reported evidence that a very high affinity interaction between the β‐amyloid peptide Aβ1‐42 and the α7 nicotinic acetylcholine receptor (α7nAChR) may be a precipitating event in the formation of amyloid plaques in Alzheimer's disease. In the present study, the kinetics for the binding of Aβ1‐42 to α7nAChR and α4β2nAChR were determined using the subtype‐selective nicotinic receptor ligands [3H]methyllycaconitine and [3H]cytisine. Synaptic membranes prepared from rat and guinea pig cerebral cortex and hippocampus were used as the source of receptors. Aβ1‐42 bound to the α7nAChR with exceptionally high affinity, as indicated by Ki values of 4.1 and 5.0 pM for rat and guinea pig receptors, respectively. When compared with the α7nAChR, the affinity of Aβ1‐42 for the α4β2nAChR was ∼5,000‐fold lower, as indicated by corresponding Ki values of 30 and 23nM. The results of this study support the concept that an exceptionally high affinity interaction between Aβ1‐42 and α7nAChR could serve as a precipitating factor in the formation of amyloid plaques and thereby contribute to the selective degeneration of cholinergic neurons that originate in the basal forebrain and project to the cortex and hippocampus.

Từ khóa


Tài liệu tham khảo

10.1016/S0166-2236(97)01144-2

10.1126/science.7046051

Bhogal N., 1994, The ligand binding site of the neurokinin 2 receptor., J. Biol. Chem., 269, 27269

10.1002/(SICI)1096-9861(19971027)387:3<385::AID-CNE5>3.0.CO;2-X

Bruss M., 1999, Pharmacological differences and similarities between the native mouse 5‐HT3 receptor in N1E‐115 cells and a cloned short splice variant of the mouse 5‐HT3 receptor expressed in HEK 293 cells., Naunyn Schmiedebergs Arch. Pharmacol., 360, 225, 10.1007/s002109900088

10.1016/0006-2952(73)90196-2

10.1016/0196-9781(95)02130-2

CourtJ.A.&PerryE.K.(1995)Distribution of nicotinic receptors in the CNS inCNS Neurotransmission Modulators: Acetylcholine(Stone T. W. ed) pp.85–104.CRC Press Boca Raton.

CourtJ.A. LloydS. PerryR.H. GriffithsM. MorrisC. JohnsonM. McKeithI.G. PerryE.K.(1996)The nicotinic cholinergic system and β‐amyloidosis inAlzheimer Disease: From Molecular Biology to Therapy(Becker R. and Giacobini E. eds) pp.275–279.Birkhäuser Boston.

10.1016/S0028-3908(98)00221-4

10.1046/j.1471-4159.1997.69010299.x

10.1038/382716a0

10.1016/S0002-9440(10)64700-1

10.1016/S0169-328X(99)00030-3

10.1016/0922-4106(94)90080-9

10.1016/0197-0186(93)90029-5

10.1046/j.1471-4159.1998.70052179.x

Kiraha T., 1998, Nicotinic receptor stimulation protects neurons against β‐amyloid toxicity., Ann. Neurol., 42, 159, 10.1002/ana.410420205

10.1016/S0014-2999(99)00679-2

Mattson M.P., 1997, Central role of oxyradicals in the mechanism of amyloid β‐peptide cytotoxicity., Alzheimers Dis. Rev., 2, 1

10.1126/science.7569895

10.1021/jm990044m

10.1046/j.1471-4159.1997.69051904.x

10.1016/S0166-2236(97)01168-5

10.1523/JNEUROSCI.17-23-09165.1997

10.1046/j.1471-4159.1994.62041399.x

Pabreza L.A., 1990, 3H]Cytisine binding to nicotinic cholinergic receptors in brain., Mol. Pharmacol., 39, 9

10.1016/S0896-6273(00)80187-7

10.1046/j.1471-4159.1999.0720230.x

Quik M., 1997, Modulation of α7 nicotinic receptor‐mediated calcium influx by nicotinic agonists., Mol. Pharmacol., 51, 499

10.1038/nm0896-864

10.1523/JNEUROSCI.13-02-00596.1993

10.1016/S0962-8924(98)01363-4

10.1111/j.1471-4159.1990.tb04905.x

10.1074/jbc.275.8.5626

Wang S., 1997, Molecular cloning and pharmacological characterization of a new galanin receptor subtype., Mol. Pharmacol., 52, 337, 10.1124/mol.52.3.337

Williams K., 1991, Developmental changes in the sensitivity of the N‐methyl‐D‐aspartate receptor to polyamines., Mol. Pharmacol., 40, 774

10.1038/382685a0

10.1073/pnas.94.10.5296

10.1038/39522

10.1126/science.2474201

10.1016/S0928-4257(98)80035-1

Thông tin
Thông tin xuất bản

Journal of Neurochemistry

Tập 75 Số 3

1155-1161

Thông tin tác giả