P2‐176: Identification of an Experimental Drug That Enhances Brain Sirtuin 1 Levels and Improves Cognition as a Potential New Therapeutic for Ad
Year: 2019
Type: article
Abstract: Decreases in brain sirtuin 1 (SirT1) are associated with aging and Alzheimer's Disease (AD) and subjects with apolipoprotein E4 (E4) may be at greater risk for this decrease. Therefore, development of small molecules that can increase brain SirT1 levels have potential as a new therapeutic approach for AD. We conducted high through screening (HTS) on a compound library, using Neuro-2a cells to assess levels of SirT1. “Hits” increasing SirT1 then underwent secondary in vitro SirT2 assay screening, and those that did not alter SirT2 were tested in the Parallel Artificial Membrane Permeability Assay (PAMPA) and in vivo pharmacokinetic (PK) analysis. Efficacy of the best, brain-penetrant candidate, A03, was then studied in aged targeted-replacement (TR) human ApoE4 and E4FAD (E4 mice crossed to the 5XFAD model of AD) mice by 56-day oral treatment, using vehicle-treated transgenic and non-transgenic mice as controls. A03 increased SirT1 levels in the hippocampi of E4FAD mice and improved memory as assessed in the Novel Object Recognition (NOR) paradigm. In the aged E4 mouse study, IHC revealed improvement in the vesicular acetylcholine transporter (VAChT). In addition, our ongoing medicinal chemistry efforts have led to the identification of several analogs that also increase SirT1 - but not SirT2 - in vitro and that are brain-penetrant. Furthermore, we have also determined the bioavailability of A03 in rats by comparison of plasma and brain levels in PK analysis after oral and IV delivery. The increase in SirT1 elicited by A03 is an important finding because such increases can suppress tau pathology [Min et al 2017] in tau model mice. Also importantly, A03 treatment elicited no side effects such as weight loss. A03, previously developed as an antidepressant and reported to show promising clinical results in dementia patients [Dehlin 1985 Acta psychiatrica Scandinavica 71:190–196] is a promising candidate to take further in pre-clinical testing and we have identified analogs that merit in vivo testing. We plan further testing of A03 and analogs in other E4-expressing AD models, including one that expresses human tau, so that effects on tau can be determined.
Source: Alzheimer s & Dementia
Institution: University of California, Los Angeles
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2981058522