Mercaptoacetamide-based class II HDAC inhibitor lowers A beta levels and improves learning and memory in a mouse model of Alzheimer's disease

Histone deacetylase inhibitors (HDACIs) alter gene expression epigenetically by interfering with the normal functions of HDAC. Given their ability to decrease A beta levels, HDACIs are a potential treatment for Alzheimer's disease (AD). However, it is unclear how HDACIs alter A beta levels. We developed two novel HDAC inhibitors with improved pharmacological properties, such as a longer half-life and greater penetration of the blood-brain barrier: mercaptoacetamide-based class II HDACI (coded as W2) and hydroxamide-based class I and IIHDACI (coded as 12) and investigated how they affect A beta levels and cognition. HDACI W2 decreased A beta 40 and A beta 42 in vitro. HDACI 12 also decreased A beta 40, but not A beta 42. We systematically examined the molecular mechanisms by which HDACIs W2 and I2 can decrease A beta levels. HDACI W2 decreased gene expression of gamma-secretase components and increased the A beta degradation enzyme Mmp2. Similarly, HDACI I2 decreased expression of beta- and gamma-secretase components and increased mRNA levels of A beta degradation enzymes. HDACI W2 also significantly decreased A beta levels and rescued learning and memory deficits in aged hAPP 3xTg AD mice. Furthermore, we found that the novel HDACI W2 decreased tau phosphorylation at Thr181, an effect previously unknown for HDACIs. Collectively, these data suggest that class II HDACIs may serve as a novel therapeutic strategy for AD. (c) 2012 Elsevier Inc. All rights reserved.