Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A beta antibody.
ABSTRACT Disruption of cholinergic neurotransmission contributes to the memory impairment that characterizes Alzheimer disease (AD). Since the amyloid cascade hypothesis of AD pathogenesis postulates that amyloid beta (A beta) peptide accumulation in critical brain regions also contributes to memory impairment, we assessed cholinergic function in transgenic mice where the human A beta peptide is overexpressed. We first measured hippocampal acetylcholine (ACh) release in young, freely moving PDAPP mice, a well-characterized transgenic mouse model of AD, and found marked A beta-dependent alterations in both basal and evoked ACh release compared with WT controls. We also found that A beta could directly interact with the high-affinity choline transporter which may impair steady-state and on-demand ACh release. Treatment of PDAPP mice with the anti-A beta antibody m266 rapidly and completely restored hippocampal ACh release and high-affinity choline uptake while greatly reducing impaired habituation learning that is characteristic of these mice. Thus, soluble "cholinotoxic" species of the A beta peptide can directly impair cholinergic neurotransmission in PDAPP mice leading to memory impairment in the absence of overt neurodegeneration. Treatment with certain anti-A beta antibodies may therefore rapidly reverse this cholinergic dysfunction and relieve memory deficits associated with early AD.
Full-textDOI: · Available from: Steven M Paul, Jun 03, 2015
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ABSTRACT: The cholinergic system is involved in learning and memory and is affected in neurodegenerative disorders such as Alzheimer’s disease. The possibility of non-invasively detecting alterations of neurotransmitter systems in the mouse brain would greatly improve early diagnosis and treatment strategies. The hypothesis of this study is that acute modulation of the cholinergic system might be reflected as altered functional connectivity (FC) and can be measured using pharmacological resting-state functional MRI (rsfMRI).NeuroImage 01/2015; 31. DOI:10.1016/j.neuroimage.2015.01.009 · 6.13 Impact Factor
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ABSTRACT: The ability to selectively control the differentiation of neural stem cells (NSCs) into cholinergic neuron in vivo would be an important step toward a cell replacement therapy. First, GFP-NSCs were induced to differentiate into cholinergic neuron-like cells (CNLs) with retinoic acid (RA) pre-induction followed by nerve growth factor (NGF) induction. Then, these CNLs were transplanted into bilateral hippocampus of APP/PS1 transgenic mice. Behavioral parameters showed by Morris Water Maze (MWM) tests and the percentages of GFP-labelled cholinergic neurons of CNLs-transplanted mice were compared with those of controls. Brain levels of choline acetyltransferase (ChAT) mRNA and proteins were analyzed by RT-PCR and Western blotting, ChAT activity and acetylcholine (ACh) concontration were also evaluated.by ChAT activity and ACh concentration assay kits. Immunofluorescence analysis showed that 80.3±1.5% NSCs differentiated into CNLs after RA pre-induction followed by NGF induction in vitro. Three months after transplantation, 82.4±6.3% CNLs differentiated into cholinergic neurons in vivo. APP/PS1 mice transplanted with CNLs showed significant improvement in learning and memory ability compared with control groups at different time points. Furthermore, CNLs transolantation dramatically increased in the expressions of ChAT mRNA and protein, as well ChAT activity and ACh concentration in APP/PS1 mice. Our findings support the prospect of using NSCs-derived CNLs in developing therapies for AD. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.Neuroscience 02/2015; 291. DOI:10.1016/j.neuroscience.2015.01.073 · 3.33 Impact Factor