RanBP9 overexpression accelerates loss of pre and postsynaptic proteins in the APΔE9 transgenic mouse brain
Authors: Madepalli K Lakshmana
Ruizhi Wang
Hongjie Wang
Shaohua Xu
Journal: PLoS ONE (2014)
Discipline: Multidisciplinary
Keywords: neurodegenerative process; Alzheimer's disease; synapses; synaptic proteins; amyloid precursor protein
Affiliations: Section of Neurobiology, Torrey Pines Institute for Molecular Studies, Port Saint Lucie, Florida, United States of America., Department of Biological Sciences, Florida Institute of Technology, Melbourne, Florida, United States of America.

Abstract:  There is now compelling evidence that the neurodegenerative process in Alzheimer's disease (AD) begins in synapses. Loss of synaptic proteins and functional synapses in the amyloid precursor protein (APP) transgenic mouse models of AD is well established. However, what is the earliest age at which such loss of synapses occurs, and whether known markers of AD progression accelerate functional deficits is completely unknown. We previously showed that RanBP9 overexpression leads to robustly increased amyloid β peptide (Aβ) generation leading to enhanced amyloid plaque burden in a mouse model of AD. In this study we compared synaptic protein levels among four genotypes of mice, i.e., RanBP9 single transgenic (Ran), APΔE9 double transgenic (Dbl), APΔE9/RanBP9 triple transgenic (Tpl) and wild-type (WT) controls. We found significant reductions in the levels of synaptic proteins in both cortex and hippocampus of 5- and 6-months-old but not 3- or 4-months-old mice. Specifically, at 5-months of age, rab3A was reduced in the triple transgenic mice only in the cortex by 25% (p&lt;0.05) and gap43 levels were reduced only in the hippocampus by 44% (p&lt;0.01) compared to wild-type (WT) controls. Interestingly, RanBP9 overexpression in the Tpl mice reduced gap43 levels by a further 31% (p&lt;0.05) compared to APΔE9 mice. RanBP9 also further decreased the levels of drebrin in the hippocampus by 32% (p&lt;0.01) and chromogranin in the cortex by 24% (p&lt;0.05) compared to APΔE9 mice. At 6-months of age, RanBP9 expression in the cortex led to further reduction of rab3A by 30% (p&lt;0.05) and drebrin by 38% (p&lt;0.01) compared to APΔE9 mice. RanBP9 also increased Aβ oligomers in the cortex at 6 months. Similarly, in the hippocampus, RanBP9 expression further reduced rab3A levels by 36% (p&lt;0.01) and drebrin levels by 33% (p&lt;0.01). Taken together these data suggest that RanBP9 overexpression accelerates loss of synaptic proteins in the mouse brain. 

Retracted: No

PubPeer comments:
 Megacorrection in April 2019. From: https: journals.plos.org plosone article?id=10.1371 journal.pone.0215713 :  After publication of this article [1], concerns were raised about Figs 1u20136. * Fig 1A: The cortex Drebrin panel and the Hippocampus Drebrin panel appear to be identical. * Fig 2A: The cortex Drebrin panel and the Hippocampus Drebrin panel appear to be identical. * The Flag-RanBP9 Cortex panel in Figure 3A appears to be identical to the Flag-RanBP Hippocampus panel in Fig 4A. * The Flag-RanBP9 Hippocampus panel in Figure 3A appears to be identical to the Flag-RanBP Cortex panel in Fig 4A. * The Chromogenin Cortex panel in Fig 4A appears to be identical to Chromogenin Hippocampus panel in Fig 4A. * Figs 5 and 6: Two pairs of u2018insetu2019 images appear to be identical to each other: * Fig 5, Cortex Rab3A protein in transgenic mouse and Fig 6, Hippocampus, Rab3A protein in WT mouse * Fig 5, Cortex, Gap43 protein in WT mouse and Fig 6, Hippocampus, Chromogranin protein in WT mouse * The inset image in the Fig 5 APdeltaE9 RanBP9 GAP43 Cortex panel does not appear to correlate with the larger image The authors acknowledge that they mistakenly re-used and mis-labeled some images during figure preparation that resulted in similarities between individual panels. Although the flag-RanBP9 blots in the Figure 3A cortex and Fig 4A hippocampus appear to be similar, the authors confirm that the blots represent independent experiments. The authors have provided replacement images for the following panels: * Fig 1A Drebrin Hippocampus panel * Fig 2A Drebrin Hippocampus panel * Fig 4A Cortex flag-RanBP9 panel * Insets in Fig 5 for Rab3A-APdE9 RanBP9, Gap43-WT, and insets in Fig 6 for Rab3A-WT, Chromogranin-WT An Academic Editor reviewed the updated figure(s) and underlying original data files and confirmed that they support the results and conclusions reported in the published article. The authors apologize for the errors in the published article and confirm that all the primary data underlying other figures in the article are available in Figshare at the following link: https: figshare.com s 7a05b8d2bebef5410bae. The authors were unable to locate the actin blot for hippocampus in Fig 1 because of accidental deletion of the original file. Of note, the last author is (or at least was at the time of reporting) an Editorial Board member of PLOS ONE. , 
 An illustration of the problems that were addressed in the correction. Figure 1A (3 months of age). * Red boxes: Fig 1A: The cortex Drebrin panel and the Hippocampus Drebrin panel appear to be identical. ![file] , 
 Figure 2A (4 months of age): * Blue boxes: Fig 2A: The cortex Drebrin panel and the Hippocampus Drebrin panel appear to be identical. ![file] , 
 * The Flag-RanBP9 Cortex panel in Figure 3A appears to be identical to the Flag-RanBP Hippocampus panel in Fig 4A. Shown here with purple boxes. * The Flag-RanBP9 Hippocampus panel in Figure 3A appears to be identical to the Flag-RanBP Cortex panel in Fig 4A. Shown here with orange boxes. ![file] , 
 * Figs 5 and 6: Two pairs of u2018insetu2019 images appear to be identical to each other: * Fig 5, Cortex Rab3A protein in transgenic mouse and Fig 6, Hippocampus, Rab3A protein in WT mouse * Fig 5, Cortex, Gap43 protein in WT mouse and Fig 6, Hippocampus, Chromogranin protein in WT mouse * The inset image in the Fig 5 APdeltaE9 RanBP9 GAP43 Cortex panel does not appear to correlate with the larger image ![file] ,