A Role for Synaptic Zinc in Activity-Dependent Aβ Oligomer Formation and Accumulation at Excitatory Synapses

被引:188
作者
Deshpande, Atul [1 ]
Kawai, Hideki [1 ]
Metherate, Raju [1 ]
Glabe, Charles G. [2 ,3 ]
Busciglio, Jorge [1 ,3 ]
机构
[1] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA
[2] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA
[3] Univ Calif Irvine, Inst Brain Aging & Dementia, Irvine, CA 92697 USA
关键词
HUMAN CORTICAL-NEURONS; AMYLOID PRECURSOR PROTEIN; LONG-TERM POTENTIATION; ALZHEIMERS-DISEASE; TRANSGENIC MICE; IN-VIVO; SECRETED OLIGOMERS; NATURAL OLIGOMERS; COMMON MECHANISM; FIBRIL FORMATION;
D O I
10.1523/JNEUROSCI.5980-08.2009
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Soluble amyloid beta oligomers (A beta Os) interfere with synaptic function and bind with high affinity to synapses, but the mechanism underlying A beta O synaptic targeting is not known. Here, we show that the accumulation of synthetic or native Alzheimer's disease (AD)-brain oligomers at synapses is regulated by synaptic activity. Electrical or chemical stimulation increased A beta O synaptic localization and enhanced oligomer formation at synaptic terminals, whereas inhibition with TTX blocked A beta O synaptic localization and reduced A beta O synaptic load. The zinc-binding 8-OH-quinoline clioquinol markedly reduced A beta O synaptic targeting, which was also reduced in brain sections of animals deficient in the synaptic vesicle zinc transporter ZnT3, indicating that vesicular zinc released during neurotransmission is critical for A beta Osynaptic targeting. Oligomers were not internalized in recycled vesicles but remained at the cell surface, where they colocalized with NR2B NMDA receptor subunits. Furthermore, NMDA antagonists blocked A beta O synaptic targeting, implicating excitatory receptor activity in oligomer formation and accumulation at synapses. In AD brains, oligomers of different size colocalized with synaptic markers in hippocampus and cortex, where oligomer synaptic accumulation correlated with synaptic loss.
引用
收藏
页码:4004 / 4015
页数:12
相关论文
共 69 条
[1]   Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Aβ [J].
Adlard, Paul A. ;
Cherny, Robert A. ;
Finkelstein, David I. ;
Gautier, Elisabeth ;
Robb, Elysia ;
Cortes, Mikhalina ;
Volitakis, Irene ;
Liu, Xiang ;
Smith, Jeffrey P. ;
Perez, Keyla ;
Laughton, Katrina ;
Li, Qiao-Xin ;
Charman, Susan A. ;
Nicolazzo, Joseph A. ;
Wilkins, Simon ;
Deleva, Karolina ;
Lynch, Toni ;
Kok, Gaik ;
Ritchie, Craig W. ;
Tanzi, Rudolph E. ;
Cappai, Roberto ;
Masters, Colin L. ;
Barnham, Kevin J. ;
Bush, Ashley I. .
NEURON, 2008, 59 (01) :43-55
[2]   Incidence and predictors of seizures in patients with Alzheimer's disease [J].
Amatniek, JC ;
Hauser, WA ;
DelCastillo-Castaneda, C ;
Jacobs, DM ;
Marder, K ;
Bell, K ;
Albert, M ;
Brandt, J ;
Stern, Y .
EPILEPSIA, 2006, 47 (05) :867-872
[3]   Characterization of copper interactions with Alzheimer amyloid β peptides:: Identification of an attomolar-affinity copper binding site on amyloid β1-42 [J].
Atwood, CS ;
Scarpa, RC ;
Huang, XD ;
Moir, RD ;
Jones, WD ;
Fairlie, DP ;
Tanzi, RE ;
Bush, AI .
JOURNAL OF NEUROCHEMISTRY, 2000, 75 (03) :1219-1233
[4]   Learning decreases Aβ*56 and tau pathology and ameliorates behavioral decline in 3xTg-AD mice [J].
Billings, Lauren M. ;
Green, Kim N. ;
McGaugh, James L. ;
LaFerla, Frank M. .
JOURNAL OF NEUROSCIENCE, 2007, 27 (04) :751-761
[5]   Intraneuronal Aβ causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice [J].
Billings, LM ;
Oddo, S ;
Green, KN ;
McGaugh, JL ;
LaFerla, FM .
NEURON, 2005, 45 (05) :675-688
[6]  
BUSH AI, 1994, J BIOL CHEM, V269, P12152
[7]   RAPID INDUCTION OF ALZHEIMER A-BETA AMYLOID FORMATION BY ZINC [J].
BUSH, AI ;
PETTINGELL, WH ;
MULTHAUP, G ;
PARADIS, MD ;
VONSATTEL, JP ;
GUSELLA, JF ;
BEYREUTHER, K ;
MASTERS, CL ;
TANZI, RE .
SCIENCE, 1994, 265 (5177) :1464-1467
[8]   Femtomole immunodetection of synthetic and endogenous amyloid-β oligomers and its application to Alzheimer's disease drug candidate screening [J].
Chang, L ;
Bakhos, L ;
Wang, ZQ ;
Venton, DL ;
Klein, WL .
JOURNAL OF MOLECULAR NEUROSCIENCE, 2003, 20 (03) :305-313
[9]   Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer's disease transgenic mice [J].
Cherny, RA ;
Atwood, CS ;
Xilinas, ME ;
Gray, DN ;
Jones, WD ;
McLean, CA ;
Barnham, KJ ;
Volitakis, I ;
Fraser, FW ;
Kim, YS ;
Huang, XD ;
Goldstein, LE ;
Moir, RD ;
Lim, JT ;
Beyreuther, K ;
Zheng, H ;
Tanzi, RE ;
Masters, CL ;
Bush, AI .
NEURON, 2001, 30 (03) :665-676
[10]   Synaptic activity regulates interstitial fluid amyloid-β levels in vivo [J].
Cirrito, JR ;
Yamada, KA ;
Finn, MB ;
Sloviter, RS ;
Bales, KR ;
May, PC ;
Schoepp, DD ;
Paul, SM ;
Mennerick, S ;
Holtzman, DM .
NEURON, 2005, 48 (06) :913-922