Abstract
Neurodegeneration associated with amyloid β (Aβ) peptide accumulation, synaptic loss, neuroinflammation, tauopathy, and memory impairments encompass the pathophysiological features of Alzheimer's disease (AD). We previously reported that the scaffolding protein RanBP9, which is overall increased in brains of AD patients, simultaneously promotes Aβ generation and focal adhesion disruption by accelerating the endocytosis of amyloid precursor protein (APP) and β1-integrin, respectively. Here, we show that RanBP9 protein levels are increased by fourfold in FAD mutant APP transgenic mice. Accordingly, RanBP9 transgenic mice demonstrate significantly increased synapse loss, neurodegeneration, gliosis, and spatial memory deficits. RanBP9 overexpression promotes apoptosis and potentiates Aβ-induced neurotoxicity independent of its capacity to promote Aβ generation. Conversely, RanBP9 reduction by siRNA or gene dosage mitigates Aβ-induced neurotoxicity. Importantly, RanBP9 activates/dephosphorylates cofilin, a key regulator of actin dynamics and mitochondria-mediated apoptosis, and siRNA knockdown of cofilin abolishes both Aβ and RanBP9-induced apoptosis. These findings implicate the RanBP9–cofilin pathway as critical therapeutic targets not only for stemming Aβ generation but also antagonizing Aβ-induced neurotoxicity.
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Abbreviations
- RanBP9:
-
Ran-binding protein 9
- APP:
-
amyloid precursor protein
- LRP:
-
low-density lipoprotein receptor-related protein
- GFAP:
-
glial fibrillary acidic protein
- BACE1:
-
beta site APP-cleaving enzyme 1
- LDH:
-
lactate dehydrogenase
- AD:
-
Alzheimer's disease
- FAD:
-
familial Alzheimer's disease
- DIV:
-
days in vitro
- PSD95:
-
postsynaptic density 95
- TUNEL:
-
terminal uridine nick-end labeling
- FACS:
-
fluorescence-activated cell sorter
- LIMK:
-
LIM kinase
- IML:
-
inner molecular layer
- SL:
-
stratum lucidum
- ADF:
-
actin-depolymerizing factor
- PTP:
-
permeability transition pore
- PI:
-
propidium iodide
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Acknowledgements
We thank Dr. Amanda Roberts for valuable help with behavioral analysis, Dr. Elisabetta Bianchi for the RanBP9 monoclonal antibody, and Dr. Mark Ginsberg for helpful discussions. This work was supported in part by the American Health Assistance Foundation (A2007-05, DE Kang), NIH/NIA (1R01AG033055-01A1, DE Kang), NIH/NIA (1K02AG031920-10A1, DE Kang), WCU-Neurocytomics Project grant from NRF (DE Kang & I Mook-Jung), NIH/NIA (1R03AG032064-01, MK Lakshmana), and NIH/NIA (1R01AG036859-01, M.K. Lakshmana).
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Woo, J., Jung, A., Lakshmana, M. et al. Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration. Cell Death Differ 19, 1413–1423 (2012). https://doi.org/10.1038/cdd.2012.14
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DOI: https://doi.org/10.1038/cdd.2012.14
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