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

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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Hippocampal ACh release in PDAPP mice is restored to WT levels after ant...
Hippocampal ACh release in PDAPP mice is restored to WT levels after anti-Aβ treatment. (A) Hippocampal ACh release in WT and PDAPP transgenic mice following exposure to a novel environment (Novelty) and after treatment of PDAPP mice with the anti-Aβ antibody m266 (PDAPP + m266; 500 μg i.p.). The arrows indicate the time at which mice were placed into a novel environment (novelty) and back into their home cage. (B) Release of ACh from the hippocampus of WT and PDAPP mice following administration of scopolamine (0.3 mg/kg i.p.) and after administration of m266. n = 7–10 mice per group, 4–6 months of age. (C) Extracellular levels of choline in brain measured by in vivo microdialysis from WT and PDAPP mice. n = 5 mice per group, 4–6 months of age. (D) Basal levels of hippocampal ACh release in WT, PDAPP, and PDAPP mice administered m266. n = 7–10 mice per group, 4–6 months of age. *P < 0.05 versus WT; #P < 0.05, PDAPP versus PDAPP + m266.