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[P4–045]: MAPTA: MODELING ALLIANCE OF SYSTEMS PHARMACOLOGY IN TAUOPATHIES — IN SILICO MODELING OF BIOMARKERS AND TARGETS
Author(s) -
Geerts Hugo
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.06.1909
Subject(s) - neuropathology , tauopathy , neuroscience , biomarker , systems pharmacology , tau protein , in silico , clinical trial , precision medicine , medicine , disease , psychology , computational biology , bioinformatics , computer science , alzheimer's disease , pharmacology , biology , neurodegeneration , pathology , drug , biochemistry , gene
was performed. Based on “The Connectivity Map”, 89 small molecules were selected for further analysis of synj1 and Ab-lowering effects using wild-type and ApoE4 neuronal cultures. The identified lead compound nimodipine was further tested in vivo using an AD transgenic mouse model (APP/PS1), and in an ApoE4 KI mouse model. Medicinal chemistry modifications of nimodipine were performed to develop analogs with increased potency at lowering synj1. Results: An FDA-approved drug nimodipine reduced synj1 protein and Ab levels both in vitro and in vivo. It also improved cognitive function in AD mouse models in short-term treatment. However, chronic administration of nimodipine failed to reduce brain Ab42 levels (particularly insoluble fractions), or to improve cognitive function. Usingmedicinal chemistry, structural analogs of nimodipinewere developed with reduced calcium channel activity and increased efficacy at improving cognitive function in vivo. One first-generation analog SynaptoCpd#9, exhibited an attenuated inhibition of calcium channels and an increased potency against synj1 and Ab42 compared to nimodipine both in vitro and in vivo. Oral administration of SynaptoCpd#9 in APP/PS1 and ApoE4 mice for 3-6 months improved cognitive function and reduced AD-related pathologies (insoluble Ab42 particularly). RNA-sequencing and qPCR studies of treated ApoE4 neurons identified three candidate genes involved in nimodipineor SynaptoCpd#9-mediated effects. Conclusions: A novel target, synj1, for AD has been identified with several benefical effects of reducing its expression characterized. Novel chemical scaffolds with medicinal chemistry modifications targeted at synj1 expression are developed toward preclinical drug candidates for AD.