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Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-Aβ antibody
Kelly R. Bales, … , Steven M. Paul, George G. Nomikos
Kelly R. Bales, … , Steven M. Paul, George G. Nomikos
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):825-832. https://doi.org/10.1172/JCI27120.
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Research Article Neuroscience

Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-Aβ antibody

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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 β (Aβ) peptide accumulation in critical brain regions also contributes to memory impairment, we assessed cholinergic function in transgenic mice where the human Aβ 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 Aβ-dependent alterations in both basal and evoked ACh release compared with WT controls. We also found that Aβ 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-Aβ 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 Aβ peptide can directly impair cholinergic neurotransmission in PDAPP mice leading to memory impairment in the absence of overt neurodegeneration. Treatment with certain anti-Aβ antibodies may therefore rapidly reverse this cholinergic dysfunction and relieve memory deficits associated with early AD.

Authors

Kelly R. Bales, Eleni T. Tzavara, Su Wu, Mark R. Wade, Frank P. Bymaster, Steven M. Paul, George G. Nomikos

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Figure 1

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Hippocampal ACh release and tissue levels are reduced in PDAPP transgeni...
Hippocampal ACh release and tissue levels are reduced in PDAPP transgenic mice. (A) Basal levels of hippocampal ACh release measured by in vivo microdialysis from WT and PDAPP transgenic mice (n = 7–10 mice per group, 4–6 months of age). (B and C) Tissue levels of ACh from the hippocampus (B) and cortex (C) of PDAPP and WT mice (n = 6 mice per group). *P < 0.05 versus WT.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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