Peptoid Antagonists of the ApoE/ABeta Interaction as a Novel Anti-ABeta Therapy.

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Project summary: This is an application for an administrative supplement to K02 AG034176 Independent Scientist Career Development Award, which was affected by the super storm Sandy. The research plan of this award pursues development of peptoid compounds blocking the interaction between Aß and apolipoprotein (apo) E as novel Alzheimer’s disease (AD) therapeutics. The career development plan outlines training in protein chemistry, synthesis of peptoid compounds, drug design and development, in vivo Aß microdialysis, gaining experience in conducting AD clinical trials, and mentoring junior faculty and PhD students. Due to flooding sustained by the NYU School Medicine campus multiple of our research facilities were temporarily closed and some still have not reopened, which compromised on campus academic and training activities. Temporary closure included our laboratory and our animal colony facility, which was flooded and became inaccessible for five weeks; therefore all efforts to breed AD transgenic (Tg) mice for planned experiments and ongoing experiments on these mice were suspended. Despite setbacks, the specific aims of the award remained unchanged. Aim I outlines development of peptoid antagonists of the apoE/Aß binding, which are designed based on the structure of Aß12- 28P, a synthetic peptide used in our preliminary study to demonstrate that pharmacological blocking of the apoE/Aß interaction prevents memory impairment and reduces Aßplaque load in AD Tg mice (Sadowski et al. PNAS 2006;103:18787). Aim II outlines treatment with Aß12-28P and its most optimal peptoid derivatives in AD Tg mice expressing various human apoE isoforms, as the preliminary study was done in mice expressing murine apoE. Aim III investigates whether blocking the apoE/Aß interaction prevents intraneuronal accumulation of Aß and improves brain Aß clearance. The research plan of this supplement builds on results, which were obtained working toward the original specific aims and proposes studies to restore losses caused by the super storm Sandy. For aim I we have a unique library of cyclic Aß12-28P derivatives with peptoid modifications which we propose to test. For aim II we have developed and characterized a novel AD Tg model mice APPSW/PS1dE9 apoE-TR with targeted replacement (TR) of the mouse apoE gene for human apoE isoforms E2, E3, and E4. Aß12-28P treatment in both APPSW/PS1dE9/apoE2-TR and APPSW/PS1dE9/apoE4-TR mice reduced brain Aß accumulation. In this supplement we plan to characterize Aß12-28P treatment in APPSW/PS1dE9/apoE3-TR line and effects of the treatment with the most promising peptoid compound in all three TR lines. For aim III we have developed a neuronal-astrocytic co-culture system to study the apoE/Aß interaction in vitro and we plan to investigate the effect of various human apoE isoforms on intraneuronal Aß pathology. Furthermore, this administrative supplement would aid to restore my original career development plan, which was disrupted in the aftermath of the super storm due to closure of multiple facilities in our campus and a need to divert personal effort from career development and training activities toward restoration of research capacity of our laboratory.