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P4‐281: Drug repositioning for Alzheimer's disease and effects of beta‐amyloid on the proteome in cell culture for Alzheimer's disease
Author(s) -
Modak Swananda,
Sims Paul,
Khan Farid,
Jin LeeWay,
Maezawa Izumi,
Doig Andrew
Publication year - 2012
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.2013.08.062
Subject(s) - toxicity , intracellular , extracellular , proteome , pharmacology , amyloid beta , cell culture , alzheimer's disease , drug discovery , microbiology and biotechnology , disease , drug , biology , chemistry , biochemistry , medicine , pathology , genetics
Background: The series of events leading from b-amyloid (Ab) aggregation to neuronal death in Alzheimer’s Disease (AD) remains poorly understood, though both extraand intracellular aggregates have been implicated. Peptidic and small molecule drugs can inhibit Ab aggregation and toxicity. Our most effective compounds can prevent synaptic damage, reduce memory deficits in a rat brain and reverse loss of Long Term Potentiation by Ab. Methods:We have compared the proteomes of SH-SY5Y cells, treated with extracellular A b42, andMC65 cells which conditionally express C99 that is subsequently cleaved to give intracellular Ab. We are currently screening libraries of previously reported drugs for other conditions to see if any can reduce Ab toxicity. Compounds are assayed for reducing Ab toxicity in SH-SY5Y cells using MTT and LDH assays. Results: We find 219 proteins that appear in Ab42 treated cells and 170 specific to Ab induced cells, both after 24 hours. 43 are common to both Ab treatments.Compound library screening shows that the Parkinson’s Disease drug A-77636, which is a D1 dopamine receptor agonist, is able to reduce Ab42 toxicity in cell culture at nM concentration.Conclusions: Proteomic data reveals hundreds of proteins implicated in Ab toxicity that have never been previously reported to be related to AD. Many are found in mitochondria.Since A77636 has already been shown to have acceptable ADMET properties and can penetrate the blood-brain-barrier, it may be possible to fast track it to clinical trials in humans.