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 P (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 and-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.
机构:Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
Cleary, JP
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Walsh, DM
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机构:Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
Walsh, DM
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Hofmeister, JJ
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机构:Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
Hofmeister, JJ
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Shankar, GM
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机构:Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
Shankar, GM
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Kuskowski, MA
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机构:Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
Kuskowski, MA
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Selkoe, DJ
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机构:Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
Selkoe, DJ
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Ashe, KH
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Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USAMinneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
机构:Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
Cleary, JP
;
Walsh, DM
论文数: 0引用数: 0
h-index: 0
机构:Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
Walsh, DM
;
Hofmeister, JJ
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h-index: 0
机构:Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
Hofmeister, JJ
;
Shankar, GM
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机构:Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
Shankar, GM
;
Kuskowski, MA
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机构:Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
Kuskowski, MA
;
Selkoe, DJ
论文数: 0引用数: 0
h-index: 0
机构:Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA
Selkoe, DJ
;
Ashe, KH
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h-index: 0
机构:
Minneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USAMinneapolis Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Minneapolis, MN 55417 USA