Background: Oxidative damage in Alzheimer disease (AD) is strongly associated with amyloid-b (Ab), a pathological hallmark of the disorder. As treatment and prevention options for dementia reach the forefront of the neuro-medical community, the benefits of antioxidant therapy are becoming increasingly evident. Sulforaphane (SFN), well-known antioxi- dants, found in broccoli and other cruciferous vegetables, is one of the most biologically active phytochemicals in the human diet. We hypothe- sized that the antioxidative activity of SFN would help protect the AD brain from brain damages induced by Ab and have significant potency as an AD therapeutic candidate. Administration of SFN ameliorated cognitive func- tion of Ab-induced AD acute mouse models in Y-maze and passive avoid- ance behavior tests. Interestingly, we found that the therapeutic effect of SFN did not involve inhibition of Ab aggregation. While the exact mecha- nism of interaction of SFN in AD has not yet been ascertained, our results suggest that SFN can aid in cognitive impairment and may protect the brain from amyloidogenic damages. Methods: 1) Transmission electron micros- copy (TEM)2) Cytotoxicity test 3) Amyloidogenesis test 4) Acute AD model (male ICR, 5.5 weeks): single intracerebroventricular (i.c.v.) injec- tion of Ab aggregates 5) Administration of SFN administration via intraper- itoneal (i.p.) injection 6) Behavior tests: Y-maze and passive avoidance (PA) tests. Results: From Y-maze and PA tests, SFN significantly improved cognitive, working memory and contextual memory of acute AD model increasing alternation and latency (Figure A , ). However, the ThT assay and TEM imaging indicated that SFN did not directly interact with Ab in its neuroprotective action (Figure B). Rather, we expect that SFN acted as a downstream protectant against Ab-induced oxidative stress in the AD brain. Conclusions: Administration of SFN ameliorated cognitive dysfunc- tion of Ab-induced AD acute mice. Since aggregation of Ab is one of the prin- ciple causes of neuronal dysfunction in the disorder, therapeutic strategies for AD have focused on development of Ab modulators affecting on abnormal production and accumulation of Ab. Although SFN did not regulate amyloi- dogenesis, the downstream protective role was noteworthy against Ab-in- duced oxidative stress. Thus, we suggest that antioxidants such as SFN can be a complementary but promising strategy to approach AD treatment. P1-031 LENALIDOMIDE AS AN ANTINEURO INFLAMMATORYAND BACE1 INHIBITOR: PILOT STUDY ON APP23 MICE Boris Decourt, Aaron Walker, Mimi Macias, Amanda Gonzales, Marwan Sabbagh, BannerSun Health Research Institute, Sun City, Arizona, United States. Contact e-mail: boris.decourt@bannerhealth.com Background: Preliminary results indicated that chronic administration of the very potent TNFa inhibitor thalidomide significantly reduces brain inflammation and amyloid pathology in APP23 transgenic mice. We hypothesized that lenalidomide, a less toxic analog of thalidomide, might rep- resent a safer alternative to treat Alzheimer’s disease (AD) in humans. Here, we are presenting new data from our pre-clinical proof of concept study col- lected in the past months. Methods: The effects of two doses of lenalidomide were evaluated: 0 and 100 mg/kg administered intraperitoneally for four weeks to APP23 mice (n¼4 and 5, respectively). Non-transgenic (WT) litter- mates were used as controls (n¼5 per dose). After sacrifice, brains were hemi- sected and used in histological and biochemical experiments. Brain sections were immunostained with an anti-amyloid beta antibody (6E10) and counter- stained with thioflavin S. Quantitative PCR and Western blotting for TNFa precursor and BACE1 were conducted on the cortex from the same animals (n¼2 APP23 and 4 WT mice per drug group). In addition, Western blots were conducted on whole half-brain lysates. Results: APP23 mice treated with 100 mg/kg lenalidomide showed w70% decrease in total (dense + dif- fuse plaques) and dense cortical amyloid plaques compared to vehicle-treated animals. The immunomodulatory efficacy of lenalidomide treatment was confirmed by a 50% decrease in cortical TNFa mRNA levels measured by qPCR. In addition, both qPCR and Western blotting also revealed a 50% and 20% decrease, respectively, in cortical and whole brain BACE1 signals after lenalidomide treatment. No change in TNFa and BACE1 levels were de- tected in WT mice after drug treatment. Conclusions: The data presented here warrant further examination of lenalidomide as both anti-inflammatory and anti-amyloid treatment for AD. Additional experiments using larger sample sizes and including cognitive/behavioral tests are in progress. If confirmed, our data will provide grounds for the rapid translation of lenalidomide for clinical application and therapeutic trials. P1-032 A SYSTEMS GENETIC APPROACH TO UNDERSTAND LATE-ONSET ALZHEIMER’S DISEASE IN MICE Gareth Howell 1 , Ileana Soto 1 , Harriet Jackson 2 , Julie Williams 3 , Greg Carter 1 , 1 The Jackson Laboratory, Bar Harbor, Maine, United States; 2 The Jackson Laboratory, Bar Harbor, Maine, United States; 3 Cardiff University, Cardiff, United Kingdom. Contact e-mail: gareth. howell@jax.org Background: Perturbations in multiple genes are likely to combine to- gether to cause late-onset Alzheimer’s disease (LOAD). To determine these critical genetic interactions, we have developed a novel systems genetic strategy that combines the strengths of human and mouse genet- ics to systematically investigate the biological processes relevant to LOAD. Our ultimate goal is to develop mouse models for LOAD and identify and validate novel drug targets. Methods: Our approach is in two phases. We are determining the expression of LOAD genes in aging mice by performing RNA in situ hybridization combined with immunoflu- orescence in brain sections from mice aged 2-24 months (phase 1). We are also identifying fundamental pathways in which LOAD genes function in brain regions by transcriptional profiling combined with computational modeling (phase 2). We are profiling the cortex and hippocampus in mice carrying mutations in single genes, pairs of genes and ultimately, sets of LOAD genes. Mutant mice are being obtained from JAX Mice and Services and the Knockout Mouse project (KOMP). AD-relevant phe- notypes are assessed using a battery of histological and behavioral assess- ments. Results: We are prioritizing LOAD genes based on our human genetic data and gene network analysis. We have generated RNA probes for the first ten LOAD genes and they show only partial over- lapping expression profiles in aging mice brains. For instance, in the CA1 region of the hippocampus from mice aged 7 months, Abca7 is expressed in both neurons and astrocytes. In contrast, Bin1 is ex- pressed almost exclusively in neurons. In phase 2, we are collecting and establishing mice mutant for eight LOAD genes. Our network analysis predicts Abca7, Bin1 and Clu (in addition to APOE4) are drivers of LOAD. Therefore, these genes have been prioritized for combinatorial transcriptional profiling and iterative computational modeling. Conclusions: We have developed a novel pipeline for the der- ivation of mouse models for LOAD. Our pipeline uses transcriptional pro- filing data from AD-relevant brain regions to construct networks describing the effects of mutations in LOAD genes. We combine the strengths of human genetics/genomics with mouse genetics/genomics that we believe is key to developing preventative treatments for Alzheim- er’s disease. Sunday, July 14, 2013: Poster Presentations: P1 P163