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

被引:93
作者
Bales, KR
Tzavara, ET
Wu, S
Wade, MR
Bymaster, FP
Paul, SM
Nomikos, GG
机构
[1] DC0533 Eli Lilly & Co, Neurosci Discovery Res, Indianapolis, IN 46285 USA
[2] Indiana Univ, Sch Med, Program Med Neurobiol, Indianapolis, IN USA
关键词
D O I
10.1172/JCI27120
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:825 / 832
页数:8
相关论文
共 40 条
[1]  
Acquas E, 1996, J NEUROSCI, V16, P3089
[2]   THE CHOLINERGIC HYPOTHESIS OF GERIATRIC MEMORY DYSFUNCTION [J].
BARTUS, RT ;
DEAN, RL ;
BEER, B ;
LIPPA, AS .
SCIENCE, 1982, 217 (4558) :408-417
[3]   Choline transporter 1 maintains cholinergic function in choline acetyltransferase haploinsufficiency [J].
Brandon, EP ;
Mellott, T ;
Pizzo, DP ;
Coufal, N ;
D'Amour, KA ;
Gobeske, K ;
Lortie, M ;
López-Coviella, I ;
Berse, B ;
Thal, LJ ;
Gage, FH ;
Blusztajn, JK .
JOURNAL OF NEUROSCIENCE, 2004, 24 (24) :5459-5466
[4]   MEASUREMENT OF ACETYLCHOLINE AND CHOLINE IN BRAIN BY HPLC WITH ELECTROCHEMICAL DETECTION [J].
BYMASTER, FP ;
PERRY, KW ;
WONG, DT .
LIFE SCIENCES, 1985, 37 (19) :1775-1781
[5]   Natural oligomers of the amyloid-protein specifically disrupt cognitive function [J].
Cleary, JP ;
Walsh, DM ;
Hofmeister, JJ ;
Shankar, GM ;
Kuskowski, MA ;
Selkoe, DJ ;
Ashe, KH .
NATURE NEUROSCIENCE, 2005, 8 (01) :79-84
[6]   ALZHEIMERS-DISEASE - A DISORDER OF CORTICAL CHOLINERGIC INNERVATION [J].
COYLE, JT ;
PRICE, DL ;
DELONG, MR .
SCIENCE, 1983, 219 (4589) :1184-1190
[7]   Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment [J].
DeKosky, ST ;
Ikonomovic, MD ;
Styren, SD ;
Beckett, L ;
Wisniewski, S ;
Bennett, DA ;
Cochran, EJ ;
Kordower, JH ;
Mufson, EJ .
ANNALS OF NEUROLOGY, 2002, 51 (02) :145-155
[8]   Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease [J].
DeMattos, RB ;
Bales, KR ;
Cummins, DJ ;
Dodart, JC ;
Paul, SM ;
Holtzman, DM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (15) :8850-8855
[9]   Behavioral disturbances in transgenic mice overexpressing the V717F β-amyloid precursor protein [J].
Dodart, JC ;
Meziane, H ;
Mathis, C ;
Bales, KR ;
Paul, SM ;
Ungerer, A .
BEHAVIORAL NEUROSCIENCE, 1999, 113 (05) :982-990
[10]   Immunization reverses memory deficits without reducing brain Aβ burden in Alzheimer's disease model [J].
Dodart, JC ;
Bales, KR ;
Gannon, KS ;
Greene, SJ ;
DeMattos, RB ;
Mathis, C ;
DeLong, CA ;
Wu, S ;
Wu, X ;
Holtzman, DM ;
Paul, SM .
NATURE NEUROSCIENCE, 2002, 5 (05) :452-457