Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer's Disease

被引:83
作者
Richard, Bernhard Clemens [1 ]
Kurdakova, Anastasiia [1 ]
Baches, Sandra [2 ]
Bayer, Thomas A. [1 ]
Weggen, Sascha [2 ]
Wirths, Oliver [1 ]
机构
[1] Univ Gottingen, Univ Med Ctr, Dept Psychiat & Psychotherapy, Div Mol Psychiat, D-37075 Gottingen, Germany
[2] Univ Dusseldorf, Dept Neuropathol, Mol Neuropathol Grp, Dusseldorf, Germany
关键词
Amyloid; axonal degeneration; behavior; intraneuronal A beta; motor deficit; spatial memory; transgenic mice; 5XFAD; AMYLOID PRECURSOR PROTEIN; A-BETA ACCUMULATION; TRANSGENIC MICE; NEURON LOSS; INTRANEURONAL A-BETA(42); AXONAL DEGENERATION; PLAQUE-FORMATION; MEMORY DEFICITS; MOTOR SIGNS; SPINAL-CORD;
D O I
10.3233/JAD-143120
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
In the present report, we extend previous findings in the 5XFAD mouse model with regard to a characterization of behavioral deficits and neuropathological alterations. We demonstrate that these mice develop a robust age-dependent motor phenotype and spatial reference memory deficits when bred to homozygosity, leading to a strongly reduced age of onset of behavioral symptoms. At postnatal day sixteen, abundant A beta PP was detected in subiculum and cortical pyramidal neurons. From six weeks on, intraneuronal A beta could be detected which was much more abundant in homozygous mice. The same gene-dosage effect was seen on memory and motor deficits. While at 2 months of age neither heterozygous nor homozygous 5XFAD mice show any neurological phenotype except for alterations in anxiety behavior, at 5 months they were clearly evident. Interestingly, despite abundant motor deficiencies, homozygous 5XFAD mice were able to perform the acquisition training of the Morris water maze task with no difference in the swimming performance between the groups. Therefore the aggravated spatial memory and spatial reference memory deficits of the homozygous mice correlated with the elevated soluble and insoluble A beta levels. Homozygous 5XFAD mice represent a model with several advantages in comparison to the heterozygous mice, developing amyloid pathology much more rapidly together with a neurological phenotype. These advantages allow reducing the number of animals for Alzheimer's disease research.
引用
收藏
页码:1223 / 1236
页数:14
相关论文
共 52 条
[1]   Transgenic Expression of Intraneuronal Aβ42 But Not Aβ40 Leads to Cellular Aβ Lesions, Degeneration, and Functional Impairment without Typical Alzheimer's Disease Pathology [J].
Abramowski, Dorothee ;
Rabe, Sabine ;
Upadhaya, Ajeet Rijal ;
Reichwald, Julia ;
Danner, Simone ;
Staab, Dieter ;
Capetillo-Zarate, Estibaliz ;
Yamaguchi, Haruyasu ;
Saido, Takaomi C. ;
Wiederhold, Karl-Heinz ;
Thal, Dietmar Rudolf ;
Staufenbiel, Matthias .
JOURNAL OF NEUROSCIENCE, 2012, 32 (04) :1273-1283
[2]   At the interface of sensory and motor dysfunctions and Alzheimer's disease [J].
Albers, Mark W. ;
Gilmore, Grover C. ;
Kaye, Jeffrey ;
Murphy, Claire ;
Wingfield, Arthur ;
Bennett, David A. ;
Boxer, Adam L. ;
Buchman, Aron S. ;
Cruickshanks, Karen J. ;
Devanand, Davangere P. ;
Duffy, Charles J. ;
Gall, Christine M. ;
Gates, George A. ;
Granholm, Ann-Charlotte ;
Hensch, Takao ;
Holtzer, Roee ;
Hyman, Bradley T. ;
Lin, Frank R. ;
Mc Kee, Ann C. ;
Morris, John C. ;
Petersen, Ronald C. ;
Silbert, Lisa C. ;
Stuble, Robert G. ;
Trojanowski, John Q. ;
Verghese, Joe ;
Wilson, Donald A. ;
Xu, Shunbin ;
Zhang, Li I. .
ALZHEIMERS & DEMENTIA, 2015, 11 (01) :70-98
[3]   Behavioral assessment of Alzheimer's transgenic mice following long-term Aβ vaccination:: Task specificity and correlations between Aβ deposition and spatial memory [J].
Arendash, GW ;
Gordon, MN ;
Diamond, DM ;
Austin, LA ;
Hatcher, JM ;
Jantzen, P ;
Dicarlo, G ;
Wilcock, D ;
Morgan, D .
DNA AND CELL BIOLOGY, 2001, 20 (11) :737-744
[4]   Deciphering the molecular profile of plaques, memory decline and neuron loss in two mouse models for Alzheimer's disease by deep sequencing [J].
Bouter, Yvonne ;
Kacprowski, Tim ;
Weissmann, Robert ;
Dietrich, Katharina ;
Borgers, Henning ;
Brauss, Andreas ;
Sperling, Christian ;
Wirths, Oliver ;
Albrecht, Mario ;
Jensen, Lars R. ;
Kuss, Andreas W. ;
Bayer, Thomas A. .
FRONTIERS IN AGING NEUROSCIENCE, 2014, 6
[5]   N-truncated amyloid β (Aβ) 4-42 forms stable aggregates and induces acute and long-lasting behavioral deficits [J].
Bouter, Yvonne ;
Dietrich, Katharina ;
Wittnam, Jessica L. ;
Rezaei-Ghaleh, Nasrollah ;
Pillot, Thierry ;
Papot-Couturier, Sophie ;
Lefebvre, Thomas ;
Sprenger, Frederick ;
Wirths, Oliver ;
Zweckstetter, Markus ;
Bayer, Thomas A. .
ACTA NEUROPATHOLOGICA, 2013, 126 (02) :189-205
[6]   APP/PS1KI bigenic mice develop early synaptic deficits and hippocampus atrophy [J].
Breyhan, Henning ;
Wirths, Oliver ;
Duan, Kailai ;
Marcello, Andrea ;
Rettig, Jens ;
Bayer, Thomas A. .
ACTA NEUROPATHOLOGICA, 2009, 117 (06) :677-685
[7]   Massive CA1/2 neuronal loss with intraneuronal and N-interminal truncated Aβ42 accumulation in a novel Alzheimer transgenic model [J].
Casas, C ;
Sergeant, N ;
Itier, JM ;
Blanchard, V ;
Wirths, O ;
van der Kolk, N ;
Vingtdeux, V ;
van de Steeg, E ;
Ret, G ;
Canton, T ;
Drobecq, H ;
Clark, A ;
Bonici, B ;
Delacourte, A ;
Benavides, J ;
Schmitz, C ;
Tremp, G ;
Bayer, TA ;
Benoit, P ;
Pradier, L .
AMERICAN JOURNAL OF PATHOLOGY, 2004, 165 (04) :1289-1300
[8]   Monoacylglycerol Lipase Is a Therapeutic Target for Alzheimer's Disease [J].
Chen, Rongqing ;
Zhang, Jian ;
Wu, Yan ;
Wang, Dongqing ;
Feng, Guoping ;
Tang, Ya-Ping ;
Teng, Zhaoqian ;
Chen, Chu .
CELL REPORTS, 2012, 2 (05) :1329-1339
[9]   Axonal degeneration in an Alzheimer mouse model is PS1 gene dose dependent and linked to intraneuronal Aβ accumulation [J].
Christensen, Ditte Z. ;
Huettenrauch, Melanie ;
Mitkovski, Miso ;
Pradier, Laurent ;
Wirths, Oliver .
FRONTIERS IN AGING NEUROSCIENCE, 2014, 6
[10]   Transient intraneuronal Aβ rather than extracellular plaque pathology correlates with neuron loss in the frontal cortex of APP/PS1KI mice [J].
Christensen, Ditte Zerlang ;
Kraus, Sophie Luise ;
Flohr, Antonius ;
Cotel, Marie-Caroline ;
Wirths, Oliver ;
Bayer, Thomas A. .
ACTA NEUROPATHOLOGICA, 2008, 116 (06) :647-655