Molecular Mechanisms of Class II HDAC inhibitors in Alzheimer's disease

Korea Brain Research Institute (Kbri), Daegu

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Abstract

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by gradual synapse and memory loss. While significant progress has been made in understanding Alzheimer's disease (AD) pathology, treatment options for AD remain limited. Therefore, further characterization of signaling pathways involved in the pathology of AD is important in facilitating the identification of new therapeutic targets. Emerging evidence postulates that epigenetic changes play critical roles in dementia. Consistent with this, inhibitors of histone deacetylases (HDACIs), such as SAHA (suberoylanilide hydroxamic acid; vorinostat), enhance neuroplasticity and memory-associated gene expression in the brain. These findings suggest that HDACIs may be novel agents in treating AD. Recently, a drug discovery team at Georgetown University has developed new Class II-specific HDAC inhibitors (mercaptoacetamide-based 6MAQH (W2), and hydroxamide-based H6CAHA (I2)), which have improved solubility and pharmacokinetic properties compared to HDACI SAHA. We have exciting preliminary data suggesting that 1) W2 decreases Ab levels in stably overexpressed APP N2A cells, 2) W2-injected hAPP 3xTg AD mice (9-10 month old, moderate Ab production) decreases Ab levels compared to control treatment, 3) W2 treatment decreases mRNA levels of A¿ synthesis enzymes and increases mRNA levels of A¿ degradation enzymes (MMP2), and 4) W2-injected hAPP 3xTg AD mice (9-10 month old, moderate memory impairment) rescued memory deficits compared to control treatment as measured by Morris Water Maze. Based on these observations, we hypothesize that Class II HDACIs (W2, I2) regulate AD pathological processes and cognitive functions by modulating the gene transcription of A¿ synthesis and degradation enzymes. To test this hypothesis, we will examine the molecular mechanisms by which W2 and I2 regulate AD pathological processes (Aim 1). We will examine the role of Class II HDACIs W2 and I2 on rescuing cognitive deficits in 3xTg AD mice (Aim 2). Results from our study will provide the molecular mechanisms of action of Class II HDACIs on Ab production, Ab plaque formation, and cognitive function for future development of AD therapeutics.