Pivotal role of the RanBP9-cofilin pathway in Aβ-induced apoptosis and neurodegeneration

Neurodegeneration associated with amyloid beta (A beta) 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 A beta generation and focal adhesion disruption by accelerating the endocytosis of amyloid precursor protein (APP) and beta 1-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 A beta-induced neurotoxicity independent of its capacity to promote A beta generation. Conversely, RanBP9 reduction by siRNA or gene dosage mitigates A beta-induced neurotoxicity. Importantly, RanBP9 activates/dephosphorylates cofilin, a key regulator of actin dynamics and mitochondria-mediated apoptosis, and siRNA knockdown of cofilin abolishes both A beta and RanBP9-induced apoptosis. These findings implicate the RanBP9-cofilin pathway as critical therapeutic targets not only for stemming A beta generation but also antagonizing A beta-induced neurotoxicity. Cell Death and Differentiation (2012) 19, 1413-1423; doi:10.1038/cdd.2012.14; published online 24 February 2012