Synaptic dysfunction and oxidative stress in Alzheimer's disease: Emerging mechanisms

被引:73
作者
Forero, D. A.
Casadesus, G.
Perry, G.
Arboleda, H.
机构
[1] Univ Nacl Colombia, Genet Inst, Bogota, Colombia
[2] Univ Nacl Colombia, Fac Med, Neurosci Grp, Bogota, Colombia
[3] Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA
[4] Univ Nacl Colombia, Fac Med, Dept Pediat, Bogota, Colombia
关键词
Alzheimer's disease; molecular genetics; neurobiology; oxidative stress; synaptic plasticity;
D O I
10.1111/j.1582-4934.2006.tb00439.x
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
In this paper, we review experimental advances in molecular neurobiology of Alzheimer's disease (AD), with special emphasis on analysis of neural function of proteins involved in AD pathogenesis, their relation with several signaling pathways and with oxidative stress in neurons. Molecular genetic studies have found that mutations in APP, PSI and PS2 genes and polymorphisms in APOE gene are implicated in AD pathogenesis. Recent studies show that these proteins, in addition to its role in beta-amyloid processing, are involved in several neuroplasticity-signaling pathways (NMDA-PKA-CREB-BDNF, reelin, wingless, notch, among others). Genomic and proteomic studies show early synaptic protein alterations in AD brains and animal models. DNA damage caused by oxidative stress is not completely repaired in neurons and is accumulated in the genes of synaptic proteins. Several functional SNPs in synaptic genes may be interesting candidates to explore in AD as genetic correlates of this synaptopathy in a "synaptogenomics" approach. Thus, experimental evidence shows that proteins implicated in AD pathogenesis have differential roles in several signaling pathways related to neuromodulation and neurotransmission in adult and developing brain. Genomic and proteomic studies support these results. We suggest that oxidative stress effects on DNA and inherited variations in synaptic genes may explain in part the synaptic dysfunction seen in AD.
引用
收藏
页码:796 / 805
页数:10
相关论文
共 106 条
[1]   A presenilin 1 mutation associated with familial frontotemporal dementia inhibits γ-secretase cleavage of APP and notch [J].
Amtul, Z ;
Lewis, PA ;
Piper, S ;
Crook, R ;
Baker, M ;
Findlay, K ;
Singleton, A ;
Hogg, M ;
Younkin, L ;
Younkin, SG ;
Hardy, J ;
Hutton, M ;
Boeve, BF ;
Tang-Wai, D ;
Golde, TE .
NEUROBIOLOGY OF DISEASE, 2002, 9 (02) :269-273
[2]   Association of neural cell adhesion molecule 1 gene polymorphisms with bipolar affective disorder in Japanese individuals [J].
Arai, M ;
Itokawa, M ;
Yamada, K ;
Toyota, T ;
Arai, M ;
Haga, S ;
Ujike, H ;
Sora, I ;
Ikeda, K ;
Yoshikawa, T .
BIOLOGICAL PSYCHIATRY, 2004, 55 (08) :804-810
[3]   Apolipoprotein E genotyping in a sample of Colombian patients with Alzheimer's disease [J].
Arboleda, GH ;
Yunis, JJ ;
Pardo, R ;
Gómez, CM ;
Hedmont, D ;
Arango, G ;
Arboleda, H .
NEUROSCIENCE LETTERS, 2001, 305 (02) :135-138
[4]   Neurodegeneration and plasticity [J].
Arendt, T .
INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE, 2004, 22 (07) :507-514
[5]   Synaptic plasticity and cell cycle activation in neurons are alternative effector pathways: the 'Dr. Jekyll and Mr. Hyde concept' of Alzheimer's disease or the yin and yang of neuroplasticity [J].
Arendt, T .
PROGRESS IN NEUROBIOLOGY, 2003, 71 (2-3) :83-248
[6]   Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals [J].
Arendt, T ;
Stieler, J ;
Strijkstra, AM ;
Hut, RA ;
Rüdiger, J ;
Van der Zee, EA ;
Harkany, T ;
Holzer, M ;
Härtig, W .
JOURNAL OF NEUROSCIENCE, 2003, 23 (18) :6972-6981
[7]   Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death [J].
Arrasate, M ;
Mitra, S ;
Schweitzer, ES ;
Segal, MR ;
Finkbeiner, S .
NATURE, 2004, 431 (7010) :805-810
[8]   Linkage analysis of Alzheimer disease with psychosis [J].
Bacanu, SA ;
Devlin, B ;
Chowdari, KV ;
DeKosky, ST ;
Nimgaonkar, VL ;
Sweet, RA .
NEUROLOGY, 2002, 59 (01) :118-120
[9]   Alzheimer's disease: one disorder, too many genes? [J].
Bertram, L ;
Tanzi, RE .
HUMAN MOLECULAR GENETICS, 2004, 13 :R135-R141
[10]   Microanatomy of dendritic spines: Emerging principles of synaptic pathology in psychiatric and neurological disease [J].
Blanpied, TA ;
Ehlers, MD .
BIOLOGICAL PSYCHIATRY, 2004, 55 (12) :1121-1127