Abstract
We previously demonstrated that overexpression of RanBP9 led to enhanced Aβ generation in a variety of cell lines and primary neuronal cultures, and subsequently, we confirmed increased amyloid plaque burden in a mouse model of Alzheimer's disease (AD). In the present study, we found striking reduction of spinophilin protein levels when RanBP9 is overexpressed. At 12 months of age, we found spinophilin levels reduced by 70% (P<0.001) in the cortex of APΔE9/RanBP9 mice compared with that in wild-type (WT) controls. In the hippocampus, the spinophilin levels were reduced by 45% (P<0.01) in the APΔE9/RanBP9 mice. Spinophilin immunoreactivity was also reduced by 22% (P<0.01) and 12% (P<0.05) in the cortex of APΔE9/RanBP9 and APΔE9 mice, respectively. In the hippocampus, the reductions were 27% (P<0.001) and 14% (P<0.001) in the APΔE9/RanBP9 and APΔE9 mice, respectively. However, in the cerebellum, spinophilin levels were not altered in either APΔE9 or APΔE9/RanBP9 mice. Additionally, synaptosomal functional integrity was reduced under basal conditions by 39% (P<0.001) in the APΔE9/RanBP9 mice and ∼23% (P<0.001) in the APΔE9 mice compared with that in WT controls. Under ATP- and KCl-stimulated conditions, we observed higher mitochondrial activity in the WT and APΔE9 mice, but lower in the APΔE9/RanBP9 mice. Significantly, we confirmed the inverse relationship between RanBP9-N60 and spinophilin in the synaptosomes of Alzheimer's brains. More importantly, both APΔE9 and APΔE9/RanBP9 mice showed impaired learning and memory skills compared to WT controls. These data suggest that RanBP9 might play a crucial role in the loss of spines and synapses in AD.
Highlights
As there can be a great variability in protein concentrations and loading of each sample, we normalized the levels of spinophilin to that of actin
The primary objective of the present study is to test whether RanBP9 overexpression in a mouse model of Alzheimer’s disease (AD) has any synaptic toxicity
Our previous observations that RanBP9 overexpression led to robust increase in the levels of amyloid b peptide (Ab) and amyloid plaque burden, which was accompanied by significant decrease in the levels of synaptic proteins,[21] formed a strong basis for the present study
Summary
At 12 months of age, we found spinophilin levels reduced by 70% (Po0.001) in the cortex of APDE9/RanBP9 mice compared with that in wild-type (WT) controls. The spinophilin levels were reduced by 45% (Po0.01) in the APDE9/RanBP9 mice. Synaptosomal functional integrity was reduced under basal conditions by 39% (Po0.001) in the APDE9/RanBP9 mice and B23% (Po0.001) in the APDE9 mice compared with that in WT controls. We confirmed the inverse relationship between RanBP9-N60 and spinophilin in the synaptosomes of Alzheimer’s brains. Both APDE9 and APDE9/RanBP9 mice showed impaired learning and memory skills compared to WT controls. We subsequently showed that RanBP9 reduced cell surface levels of APP, LRP, and b1-integrin, resulting in strongly enhanced Ab generation and focal adhesion disruption.[4,6] Surprisingly, RanBP9-N60, a 60-kDa proteolytically derived species of RanBP9 that binds to APP, LRP and BACE-1 stronger than that of the full-length protein, was increased six-fold in the brains of patients with
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
