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Is beta‐arrestin related to muscarinic receptor uncoupling in Alzheimer's disease? (153.4)
Author(s) -
Potter Pamela,
Bills Matthew,
Killpack Luke,
Hamada Matthew,
Jones Douglas,
Sue Lucia,
Beach Thomas
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.153.4
Subject(s) - muscarinic acetylcholine receptor , senile plaques , endocrinology , medicine , alzheimer's disease , cholinergic , receptor , choline acetyltransferase , muscarinic acetylcholine receptor m1 , muscarinic acetylcholine receptor m3 , amyloid (mycology) , biology , chemistry , pathology , disease
The purpose of this study was to characterize the mechanism underlying muscarinic receptor uncoupling in patients with Alzheimer’s disease. We found previously that muscarinic receptors were uncoupled from G‐ proteins in brains of patients with Alzheimer’s disease, as well as in non‐demented controls with substantial β‐amyloid deposition and neuritic plaque formation 1 . We also have found that as plaque levels and β‐amyloid increased, levels of the G‐protein coupled receptor kinase GRK‐2 were significantly decreased, and Gq/11 protein was shifted from the cytosol to the membrane fraction. In the current study, levels of β‐arrestin, a protein involved in receptor recycling, were examined in four groups: patients diagnosed with Alzheimer’s (AD), age matched controls with many plaques (MP), age matched controls with sparse plaques (SP), and age‐matched controls with no plaques (NP). The amount of plaque formation was correlated with loss of cholinergic neurons as assessed by choline acetyltransferase (ChAT) activity. Levels of signal transduction markers were measured using Western blot. Levels of β‐amyloid were measured using ELISA. We found that β‐arrestin levels were decreased in both non‐demented groups with neuritic plaques as well as in those with Alzheimer’s disease, compared to the control group. It is likely that alterations in GRK, coupled with a decrease in β‐arrestin, could impair muscarinic receptor recycling. Loss of recycling could lead to downregulation or uncoupling of the receptors. Thus, it may be very important to attempt to circumvent impairment of signal transduction by addressing cholinergic dysfunction in treatment of Alzheimer’s disease. 1. Potter PE, Rauschkolb PK, Pandya Y, Sue LI, Sabbagh MN, Walker DG, Beach TG. Acta Neuropathol . 122:49‐60, 2011 2. Beach, T.G., Potter, P.E., Kuo, Y.‐M., Emmerling, M.R., Durham, R.A., Webster, S.D., Walker, D.G., Sue, L.I., Scott, S., Layne, K.J. and Roher, A.E. Neurosci. Lett. 283, 9‐12, 2000