Abstract Details

Title Prostate Cancer Drug IRX Attenuates Cognitive Deterioration in Alzheimer's Disease through CREB Signaling

Topic Aging and Dementia

Presentation(s) IN11 - (-)

Poster/Presentation
Number 001

Objective

Background AD is characterized neuropathologically by accumulation of extracellular plaques composed of Abeta protein, intracellular neurofibrillary tangles of hyperphosphorylated tau protein, and neuron loss. Growing evidence suggests cognitive deterioration in AD is directly linked to accumulation of extracellular soluble oligomeric Abeta species. Oligomeric Abeta induces synapse degeneration, synaptic plasticity disruption and decreased long-term potentiation (LTP), which contribute to mechanisms underlying the onset and progression of dementia in AD.

Design/Methods Photo-induced cross-linking of unmodified protein (PICUP). Primary neurons and primary astrocytes were used to evaluate ApoE expression following IRX treatment. Electrophysiology recording was used to evaluate effects of IRX on synaptic plasticity. Young TgCRND8 mouse model of AD was used to evaluate short-term in vivo efficacy of IRX. Morris water maze test and the contextual fear conditioning test were used to evaluate cognitive function.

Results Our preliminary studies showed that similar to Bexarotene, IRX can significantly induce ApoE expression in neurons and astrocytes, which may improve ApoE-mediated Abeta clearance. Contrary to IRX4204, Bexarotene was unable to interfere with Abeta and tau protein aggregation and improve synaptic plasticity through CREB-signaling pathway. In a short-term feasibility study, we found daily oral administration of IRX4204 for 10 days resulted in a steady level of IRX4204 in the brain, which is capable of eliciting CREB pathways.

Conclusions Our data suggest that the benefits of IRX4204 might be attributed to the anti-oligomerization activity of IRX4204, which may neuroprotect against aggregated Abeta toxicity, ultimately rescuing LTP, coincidental with preservation of cognitive function.

Authors/Disclosures
Giulio M. Pasinetti, MD, PhD (Mount Sinai School of Medicine) PRESENTER	No disclosure on file
Mark S. Freedman, MD, FAAN (University of Ottawa)	Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Actelion(Janssen/J&J). Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BiogenIdec. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS/Celgene. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Inc. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Actelion (Janssen/J&J). Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Atara Biotherapeutics. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer Healthcare. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for BiogenIdec. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Clene Nanomedicine. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GRI Bio. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Magenta Therapeutics. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Freedman has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi Genzyme. Dr. Freedman has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD Serono. The institution of Dr. Freedman has received research support from Sanofi Genzyme.

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