Novel CNS Transporter Target in Alzheimer's Disease
Dr. Tae-Wan Kim and colleagues have identified an 'atypical monoamine transporter' as a novel therapeutic target in Alzheimer's disease. The proposed research is designed to further validate the new target and generate therapeutic lead compounds. Further research will be conducted to understand this target in greater depth, using cell biological approaches.
Alzheimer's disease (AD) is characterized pathologically in the brain by the accumulation and deposition of amyloid beta-peptide (Abeta), a small protein with a high propensity for aggregation and neuro-toxic effects. The production of Abeta is controlled by the cleavage of amyloid precursor protein (APP) by two enzymes, beta-secretase (BACE1) and gamma-secretase. A major focus of drug development for AD has been to inhibit these enzymes directly, in order to preclude the liberation of Abeta from APP. However, major late-stage clinical trials have been disappointing due to lack of efficacy or side effects of these drugs in humans.
Since directly targeting BACE1 and gamma-secretase has proven largely ineffective, new molecular targets must be identified that can reduce brain Abeta levels through alternate pathways. In order to identify novel pathways for disruption of Abeta production, Dr. Tae-Wan Kim's team has developed a novel screening strategy using intact neuronal cells harboring a fluorescent reporter of BACE1 cleavage of APP. This approach allows identification of completely new pathways for regulating Abeta production. Using this strategy, they identified multiple small-molecule chemical compounds that reduced APP cleavage in intact cells but did not inhibit BACE1 directly. This approach allows the identification of a completely new pathway for regulating Abeta production. The cellular target of this lead compound has not yet been identified, and this information is critical to fully exploit the newly discovered cellular pathway for regulation of Abeta production.
The goal of this study is to identify the cellular target of this new small molecule. Based on preliminary data, the research team hypothesizes that the target is a member of a class of neurotransmitter transporters. This is a highly “drug-able” class of transporters that has previously been targeted in treatments for depression and drug addiction, but not yet explored for AD. Dr. Kim's team will determine if the compound binds directly to the putative target transporter, critical data for future drug development, as well as determine the molecular and cellular pathways harnessed by this new compound for Abeta reduction.
Since this newly identified compound targets a novel cellular pathway in neurons known to be vulnerable in AD, completion of these studies will lay the groundwork for future development of this lead compound into a drug candidate. This study will also introduce the field to a completely novel cellular mechanism for critically lowering Abeta production and explore a new strategy for developing AD therapeutics.