Molecular pathways underlying the neurotoxicity and production of amyloid β protein (Aβ) represent potentially promising therapeutic targets for Alzheimer's disease (AD). We recently found that overexpression of the scaffolding protein RanBP9 increases Aβ 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 Aβ-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 Aβ-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 Aβ 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 Aβ accumulation but also in mediating the neurotoxic actions of Aβ at the level of synaptic plasticity, mitochondria, and cofilin–actin pathology via control of the SSH1-cofilin pathway in vivo.

Mitochondrial dysfunction and synaptic damage are important features of Alzheimer's disease (AD) associated with amyloid β (Aβ) and tau. We reported previously that the scaffolding protein RanBP9, which is overall increased in brains of patients with AD and in mutant APP transgenic mice, simultaneously promotes Aβ generation and focal adhesion disruption by accelerating the endocytosis of APP and β1-integrin, respectively. Moreover, RanBP9 induces neurodegeneration in vitro and in vivo and mediates Aβ-induced neurotoxicity. Here we show in primary hippocampal neurons that RanBP9 potentiates Aβ-induced reactive oxygen species (ROS) overproduction, apoptosis, and calcium deregulation. Analyses of calcium-handling measures demonstrate that RanBP9 selectively delays the clearance of cytosolic Ca(2+) mediated by the mitochondrial calcium uniporter through a process involving the translocation of cofilin into mitochondria and oxidative mechanisms. Further, RanBP9 retards the anterograde axonal transport of mitochondria in primary neurons and decreases synaptic mitochondrial activity in brain. These data indicate that RanBP9, cofilin, and Aβ mimic and potentiate each other to produce mitochondrial dysfunction, ROS overproduction, and calcium deregulation, which leads to neurodegenerative changes reminiscent of those seen in AD.

Background: The BRIDGE Clinic began a Colon Cancer Screening Program in 2012 that has continued to provide the local underserved community with free colon cancer screening. This program allows BRIDGE Clinic to provide preventative care in accordance with the United States Preventative Services Task Force guidelines for colorectal cancer screening. The purpose of this study was to investigate the demographics of participants and the outcomes of the colorectal cancer screening program at BRIDGE Clinic and compare this information to 2015 National Health Interview Survey data.Methods: This study was a retrospective analysis of the medical records of patients eligible for routine colorectal cancer screening. Patients aged 50-75 years and who had at least one clinic visit at BRIDGE between January 2012 and December 2015 were included. Demographics, screening method, and outcome information were extracted by chart review.Results: A total of 133 uninsured patients were eligible. Of those patients who qualified for colorectal cancer screening, 64% were screened (34% with fecal immunochemical testing, 66% with colonoscopy). Among those screened with colonoscopy, one (2%) patient had rectal carcinoma in situ, 10 (18%) patients had pre-cancerous polyps, 19 (34%) patients had benign hyperplastic polyps (34%), and 26 (46%) had normal colonoscopies.Conclusions: The Colon Cancer Screening Program at the BRIDGE Clinic has facilitated a screening rate of 64%, a rate that is close to three times the national average for uninsured patients (22%) and almost at the national average for insured patients (65%). This suggests it is feasible for free clinics to achieve high colorectal cancer screening rates if strong community partnerships and a clear process are in place.

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