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Molecular pathways underlying the neurotoxicity and production of amyloid  β  protein (A β ) represent potentially promising therapeutic targets for Alzheimer's disease (AD). We recently found that overexpression of the scaffolding protein RanBP9 increases A β  production in cell lines and in transgenic mice while promoting cofilin activation and mitochondrial dysfunction. Translocation of cofilin to mitochondria and induction of cofilin–actin pathology require the activation/dephosphorylation of cofilin by Slingshot homolog 1 (SSH1) and cysteine oxidation of cofilin. In this study, we found that endogenous RanBP9 positively regulates SSH1 levels and mediates A β -induced translocation of cofilin to mitochondria and induction of cofilin–actin pathology in cultured cells, primary neurons, and  in vivo . Endogenous level of RanBP9 was also required for A β -induced collapse of growth cones in immature neurons (days  in vitro  9 (DIV9)) and depletion of synaptic proteins in mature neurons (DIV21).  In vivo , amyloid precursor protein (APP)/presenilin-1 (PS1) mice exhibited 3.5-fold increased RanBP9 levels, and RanBP9 reduction protected against cofilin–actin pathology, synaptic damage, gliosis, and A β  accumulation associated with APP/PS1 mice. Brains slices derived from APP/PS1 mice showed significantly impaired long-term potentiation (LTP), and RanBP9 reduction significantly enhanced paired pulse facilitation and LTP, as well as partially rescued contextual memory deficits associated with APP/PS1 mice. Therefore, these results underscore the critical importance of endogenous RanBP9 not only in A β  accumulation but also in mediating the neurotoxic actions of A β  at the level of synaptic plasticity, mitochondria, and cofilin–actin pathology via control of the SSH1-cofilin pathway  in vivo .

RanBP9 at the intersection between cofilin and Aβ pathologies: rescue of neurodegenerative changes by RanBP9 reduction