Evidence for normal aging of the septo-hippocampal cholinergic system in apoE (-/-) mice but impaired clearance of axonal degeneration products following injury

被引:101
作者
Fagan, AM [1 ]
Murphy, BA
Patel, SN
Kilbridge, JF
Mobley, WC
Bu, GJ
Holtzman, DM
机构
[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Ctr Study Nervous Syst Injury, St Louis, MO 63110 USA
[4] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA
[5] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA
[6] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA
[7] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA
关键词
aging; apolipoprotein E; basal forebrain cholinergic neurons; cholesterol; degeneration; entorhinal cortex; fimbria-fornix; hippocampus;
D O I
10.1006/exnr.1998.6818
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The association of the epsilon 4 allele of apoE with increased risk for Alzheimer's disease (AD) and with poor clinical outcome after certain acute brain injuries has sparked interest in the neurobiology of apoE. ApoE (-/-) mice provide a tool to investigate the role of apoE in the nervous system in vivo. Since integrity of the basal forebrain cholinergic system is severely compromised in AD, with severity of dysfunction correlating with apoE4 gene dosage, the present study tested the hypothesis that apoE is required to maintain the normal integrity of basal forebrain cholinergic neurons (BFCNs). Histological and biochemical analyses of the septo-hippocampal cholinergic system were performed in apoE (-/-) mice during aging and following injury. Using unbiased quantitative methods, there was little or no evidence for defects in the septo-hippocampal cholinergic system, as assessed by p75(NTR)-immunoreactive neuron number and size in the medial septum, cholinergic fiber density in the hippocampus, and choline acetyltransferase activity in the hippocampus, cortex, and striatum in aged apoE (-/-) mice (up to 24 months of age) as compared to age-matched wild-type mice of the same strain. In addition, cholinergic neuronal survival and size following fimbria-fornix transection in apoE (-/-) mice did not differ from controls. However, following entorhinal cortex lesion, there was persistence of degeneration products in the deafferented hippocampus in apoE (-/-) mice. These data suggest that although apoE is not required for the maintenance of BFCNs in vivo, it may play a role in the clearance of cholesterol-laden neurodegeneration products following brain injury. (C) 1998 Academic Press.
引用
收藏
页码:314 / 325
页数:12
相关论文
共 74 条
[1]   APOE GENOTYPE AND SURVIVAL FROM INTRACEREBRAL HEMORRHAGE [J].
ALBERTS, MJ ;
GRAFFAGNINO, C ;
MCCLENNY, C ;
DELONG, D ;
STRITTMATTER, W ;
SAUNDERS, AM ;
ROSES, AD .
LANCET, 1995, 346 (8974) :575-575
[2]   Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition [J].
Bales, KR ;
Verina, T ;
Dodel, RC ;
Du, YS ;
Altstiel, L ;
Bender, M ;
Hyslop, P ;
Johnstone, EM ;
Little, SP ;
Cummins, DJ ;
Piccardo, P ;
Ghetti, B ;
Paul, SM .
NATURE GENETICS, 1997, 17 (03) :263-264
[3]   STABLE EXPRESSION AND SECRETION OF APOLIPOPROTEINS E3 AND E4 IN MOUSE NEUROBLASTOMA-CELLS PRODUCES DIFFERENTIAL-EFFECTS ON NEURITE OUTGROWTH [J].
BELLOSTA, S ;
NATHAN, BP ;
ORTH, M ;
DONG, LM ;
MAHLEY, RW ;
PITAS, RE .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (45) :27063-27071
[4]   Amyloid beta-peptide is transported on lipoproteins and albumin in human plasma [J].
Biere, AL ;
Ostaszewski, B ;
Stimson, ER ;
Hyman, BT ;
Maggio, JE ;
Selkoe, DJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (51) :32916-32922
[5]   APOLIPOPROTEIN-E ASSOCIATED WITH ASTROCYTIC GLIA OF THE CENTRAL NERVOUS-SYSTEM AND WITH NONMYELINATING GLIA OF THE PERIPHERAL NERVOUS-SYSTEM [J].
BOYLES, JK ;
PITAS, RE ;
WILSON, E ;
MAHLEY, RW ;
TAYLOR, JM .
JOURNAL OF CLINICAL INVESTIGATION, 1985, 76 (04) :1501-1513
[6]  
Cavalieri, 1966, GEOMETRIA INDIVISIBI
[7]   Motor and cognitive deficits in apolipoprotein E-deficient mice after closed head injury [J].
Chen, Y ;
Lomnitski, L ;
Michaelson, DM ;
Shohami, E .
NEUROSCIENCE, 1997, 80 (04) :1255-1262
[8]   GENE DOSE OF APOLIPOPROTEIN-E TYPE-4 ALLELE AND THE RISK OF ALZHEIMERS-DISEASE IN LATE-ONSET FAMILIES [J].
CORDER, EH ;
SAUNDERS, AM ;
STRITTMATTER, WJ ;
SCHMECHEL, DE ;
GASKELL, PC ;
SMALL, GW ;
ROSES, AD ;
HAINES, JL ;
PERICAKVANCE, MA .
SCIENCE, 1993, 261 (5123) :921-923
[9]   ALZHEIMERS-DISEASE - A DISORDER OF CORTICAL CHOLINERGIC INNERVATION [J].
COYLE, JT ;
PRICE, DL ;
DELONG, MR .
SCIENCE, 1983, 219 (4589) :1184-1190
[10]  
DAVIES P, 1976, LANCET, V2, P1403