BACE1 (β-secretase) transgenic neurochernical deficits ind knockout mice:: identification of and behavioral changes

被引:133
作者
Harrison, SM
Harper, AJ
Hawkins, J
Duddy, G
Grau, E
Pugh, PL
Winter, PH
Shilliam, CS
Hughes, ZA
Dawson, LA
Gonzalez, MI
Upton, N
Pangalos, MN
Dingwall, C
机构
[1] GlaxoSmithKline, Neurol & Gastroenterol Ctr Excellence Drug Discov, Harlow CM19 5AW, Essex, England
[2] GlaxoSmithKline, Dept Comparat Genom, Harlow CM19 5AW, Essex, England
[3] Sanger Ctr, Hinxton CB10 1SA, Cambs, England
[4] GlaxoSmithKline, Psychiat Ctr Excellence Drug Discovery, Harlow CM19 5AW, Essex, England
关键词
D O I
10.1016/S1044-7431(03)00227-6
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
BACE1 is a key enzyme in the generation of Abeta, the major component of senile plaques in the brains of Alzheimer's disease patients. We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-length coding sequence of human BACE1 preceding an internal ribosome entry site element followed by a LacZ reporter gene. These animals exhibit a bold, exploratory behavior and show elevated 5-hydroxytryptamine turnover. We have also generated a knockout mouse in which LacZ replaces the first exon of murine BACE1. Interestingly these animals show a contrasting behavior, being timid and less exploratory. Despite these clear differences both mouse lines are viable and fertile with no changes in morbidity. These results suggest an unexpected role for BACE1 in neurotransmission, perhaps through changes in amyloid precursor protein processing and Abeta levels. (C) 2003 Elsevier Inc. All rights reserved.
引用
收藏
页码:646 / 655
页数:10
相关论文
共 51 条
[1]  
Anderson IM, 1999, ADV EXP MED BIOL, V467, P43
[2]  
[Anonymous], 1994, MANIPULATING MOUSE E
[3]  
ARAI H, 1991, INT CONGR SER, V968, P131
[4]   TESTS FOR EMOTIONALITY IN RATS AND MICE - REVIEW [J].
ARCHER, J .
ANIMAL BEHAVIOUR, 1973, 21 (MAY) :205-235
[5]   Selective nicotinic receptor consequences in APPSWE transgenic mice [J].
Bednar, I ;
Paterson, D ;
Marutle, A ;
Pham, TM ;
Svedberg, M ;
Hellström-Lindahl, E ;
Mousavi, M ;
Court, J ;
Morris, C ;
Perry, E ;
Mohammed, A ;
Zhang, X ;
Nordberg, A .
MOLECULAR AND CELLULAR NEUROSCIENCE, 2002, 20 (02) :354-365
[6]  
Blier P, 2001, J PSYCHIATR NEUROSCI, V26, P37
[7]   Expression of human β-secretase in the mouse brain increases the steady-state level of β-amyloid [J].
Bodendorf, U ;
Danner, S ;
Fischer, F ;
Stefani, M ;
Sturchler-Pierrat, C ;
Wiederhold, KH ;
Staufenbiel, M ;
Paganetti, P .
JOURNAL OF NEUROCHEMISTRY, 2002, 80 (05) :799-806
[8]   Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice [J].
Bondolfi, L ;
Calhoun, M ;
Ermini, F ;
Kuhn, HG ;
Wiederhold, KH ;
Walker, L ;
Staufenbiel, M ;
Jucker, M .
JOURNAL OF NEUROSCIENCE, 2002, 22 (02) :515-522
[9]   BACE1 is the major β-secretase for generation of Aβ peptides by neurons [J].
Cai, HB ;
Wang, YS ;
McCarthy, D ;
Wen, HJ ;
Borchelt, DR ;
Price, DL ;
Wong, PC .
NATURE NEUROSCIENCE, 2001, 4 (03) :233-234
[10]   CORTICAL-NEURONS IMMUNOREACTIVE WITH ANTISERA AGAINST NEUROPEPTIDE-Y ARE ALTERED IN ALZHEIMERS-TYPE DEMENTIA .2. [J].
CHANPALAY, V ;
LANG, W ;
ALLEN, YS ;
HAESLER, U ;
POLAK, JM .
JOURNAL OF COMPARATIVE NEUROLOGY, 1985, 238 (04) :390-400