Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-Aβ antibody
Kelly R. Bales, Eleni T. Tzavara, Su Wu, Mark R. Wade, Frank P. Bymaster, Steven M. Paul, George G. Nomikos
Kelly R. Bales, Eleni T. Tzavara, Su Wu, Mark R. Wade, Frank P. Bymaster, Steven M. Paul, George G. Nomikos
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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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Aβ interacts with ChT-1. (A and B) High-affinity choline uptake into rat...
Aβ interacts with ChT-1. (A and B) High-affinity choline uptake into rat synaptosomes (A) and a cell line expressing the human ChT-1 (B) was significantly increased after exposure to Aβ42. Data are the percent of choline uptake in untreated, control samples (mean ± SEM of triplicate values) from 1 representative experiment, which was repeated 2–3 times with similar results. *P < 0.05. (C) ChT-1 was coimmunoprecipitated from hippocampal extracts by the anti-Aβ antibody 4G8 followed by Western blot analysis with an anti–ChT-1 antibody. (D) The Aβ peptide was coimmunoprecipitated from hippocampal extracts prepared from PDAPP transgenic mice by an anti–ChT-1 antibody followed by Western blot analysis with biotinylated anti-Aβ antibodies 21F12 and 2G3. (E) The anti-Aβ42 antibody 21F12, but not the anti-Aβ40 antibody 2G3, coimmunoprecipitated ChT-1 from hippocampal extracts prepared from PDAPP transgenic mice followed by Western blot analysis with an anti–ChT-1 antibody. (F) Neither an irrelevant IgG nor an anti–glutamate 1 transporter antibody (EAAT-1) coimmunoprecipitated Aβ from hippocampal extracts prepared from PDAPP mice, whereas Aβ was readily detected following immunoprecipitation with an antibody directed toward ChT-1 followed by Western blot analysis with an anti-Aβ antibody.