Alzheimer's Disease: Targeting the Cholinergic System

被引:1129
作者
Ferreira-Vieira, Talita H. [1 ]
Guimaraes, Isabella M. [1 ]
Silva, Flavia R. [1 ]
Ribeiro, Fabiola M. [1 ]
机构
[1] Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Bioquim & Imunol, Ave Antonio Carlos 6627, BR-31270901 Belo Horizonte, MG, Brazil
关键词
Acetylcholine; AChE; Alzheimer's disease; ChAT; CHT1; VAChT; VESICULAR ACETYLCHOLINE TRANSPORTER; SPATIAL WORKING-MEMORY; RIVASTIGMINE TRANSDERMAL PATCH; AMYLOID PRECURSOR PROTEIN; BASAL FOREBRAIN LESIONS; M1 MUSCARINIC AGONISTS; CENTRAL-NERVOUS-SYSTEM; VOLTAGE-CLAMP ANALYSIS; NUCLEUS BASALIS; CHOLINESTERASE-INHIBITORS;
D O I
10.2174/1570159X13666150716165726
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Acetylcholine (ACh) has a crucial role in the peripheral and central nervous systems. The enzyme choline acetyltransferase (ChAT) is responsible for synthesizing ACh from acetyl-CoA and choline in the cytoplasm and the vesicular acetylcholine transporter (VAChT) uptakes the neurotransmitter into synaptic vesicles. Following depolarization, ACh undergoes exocytosis reaching the synaptic cleft, where it can bind its receptors, including muscarinic and nicotinic receptors. ACh present at the synaptic cleft is promptly hydrolyzed by the enzyme acetylcholinesterase (AChE), forming acetate and choline, which is recycled into the presynaptic nerve terminal by the high-affinity choline transporter (CHT1). Cholinergic neurons located in the basal forebrain, including the neurons that form the nucleus basalis of Meynert, are severely lost in Alzheimer's disease (AD). AD is the most ordinary cause of dementia affecting 25 million people worldwide. The hallmarks of the disease are the accumulation of neurofibrillary tangles and amyloid plaques. However, there is no real correlation between levels of cortical plaques and AD-related cognitive impairment. Nevertheless, synaptic loss is the principal correlate of disease progression and loss of cholinergic neurons contributes to memory and attention deficits. Thus, drugs that act on the cholinergic system represent a promising option to treat AD patients.
引用
收藏
页码:101 / 115
页数:15
相关论文
共 273 条
[1]   Muscarinic receptor subtype selective toxins [J].
Adem, A ;
Karlsson, E .
LIFE SCIENCES, 1997, 60 (13-14) :1069-1076
[2]   ALTERNATIVE SPLICING LEADS TO 2 CHOLINERGIC PROTEINS IN CAENORHABDITIS-ELEGANS [J].
ALFONSO, A ;
GRUNDAHL, K ;
MCMANUS, JR ;
ASBURY, JM ;
RAND, JB .
JOURNAL OF MOLECULAR BIOLOGY, 1994, 241 (04) :627-630
[3]   THE CAENORHABDITIS-ELEGANS UNC-17 GENE - A PUTATIVE VESICULAR ACETYLCHOLINE TRANSPORTER [J].
ALFONSO, A ;
GRUNDAHL, K ;
DUERR, JS ;
HAN, HP ;
RAND, JB .
SCIENCE, 1993, 261 (5121) :617-619
[4]  
Alzheimer A., 1907, Zentralbl. Nervenh. Psych, V64, P146, DOI DOI 10.1002/CA.980080612
[5]  
ANDERSON DC, 1983, MOL PHARMACOL, V24, P48
[6]   Impairment of cholinergic neurotransmission in adult and aged transgenic Tg2576 mouse brain expressing the Swedish mutation of human β-amyloid precursor protein [J].
Apelt, J ;
Kumar, A ;
Schliebs, R .
BRAIN RESEARCH, 2002, 953 (1-2) :17-30
[7]   Increased capacity and density of choline transporters situated in synaptic membranes of the right medial prefrontal cortex of attentional task-performing rats [J].
Apparsundaram, S ;
Martinez, V ;
Parikh, V ;
Kozak, R ;
Sarter, M .
JOURNAL OF NEUROSCIENCE, 2005, 25 (15) :3851-3856
[8]   REGIONAL DISTRIBUTION OF CHOLINE-ACETYLTRANSFERASE IN HUMAN BRAIN - CHANGES IN HUNTINGTONS-CHOREA [J].
AQUILONIUS, SM ;
ECKERNAS, SA ;
SUNDWALL, A .
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, 1975, 38 (07) :669-677
[9]   LOSS OF NEURONS IN THE NUCLEUS BASALIS OF MEYNERT IN ALZHEIMERS-DISEASE, PARALYSIS AGITANS AND KORSAKOFFS DISEASE [J].
ARENDT, T ;
BIGL, V ;
ARENDT, A ;
TENNSTEDT, A .
ACTA NEUROPATHOLOGICA, 1983, 61 (02) :101-108
[10]   DISTRIBUTION OF CHOLINERGIC NEURONS IN RAT-BRAIN - DEMONSTRATED BY THE IMMUNOCYTOCHEMICAL LOCALIZATION OF CHOLINE-ACETYLTRANSFERASE [J].
ARMSTRONG, DM ;
SAPER, CB ;
LEVEY, AI ;
WAINER, BH ;
TERRY, RD .
JOURNAL OF COMPARATIVE NEUROLOGY, 1983, 216 (01) :53-68