Inhibitors of Class 1 Histone Deacetylases Reverse Contextual Memory Deficits in a Mouse Model of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by cognitive impairments that progress to dementia and death. The earliest symptoms of AD present as a relatively pure deficit in memory retrieval. Therefore, drug treatments that intervene in the early stages of AD by rescuing memory deficits could be promising therapies to slow, or even reverse progression of the disease. In this study, we tested the potential of systemic histone deacetylase inhibitor (HDACi) treatment to rescue cognitive deficits in a mouse model of AD. APPswe/PS1dE9 mice showed pronounced contextual memory impairments beginning at 6 months of age. Chronic HDACi injections (2-3 weeks) did not alter contextual memory formation in normal mice, but had profound effects in transgenic animals. Injections of sodium valproate, sodium butyrate, or vorinostat (suberoylanilide hydroxamic acid; Zolinzas) completely restored contextual memory in these mutant mice. Further behavioral testing of the HDACi-treated transgenic mice showed that the newly consolidated memories were stably maintained over a 2-week period. Measurement of the HDAC isoform selectivity profile of sodium valproate, sodium butyrate, and vorinostat revealed the common inhibition of class I HDACs (HDAC1, 2, 3, 8) with little effect on the class IIa HDAC family members (HDAC4, 5, 7, 9) and inhibition of HDAC6 only by vorinostat. These preclinical results indicate that targeted inhibition of class I HDAC isoforms is a promising avenue for treating the cognitive deficits associated with early stage AD.

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

“…Female transgenic mice were used because female mice manifest an early deficit in spatial memory in the MWM test and develop greater Aβ burden compared to age‐matched male mice (Gallagher et al ., 2013). The 4.5‐month‐old mice were selected because this transgenic line develops amyloid plaque by 4–6 months of age (Yan et al ., 2009), and memory deficits as early as 6 months of age by contextual fear conditioning test (Kilgore et al ., 2010). The 4.5‐month‐old mice are suitable for investigating the effect of intranasal insulin on early Aβ pathology.…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Indirectly enhancing histone acetylation by chronic inhibition of histone deacetylases (HDACs) was able to reverse the cognitive deficits in AD mouse model (Kilgore et al, 2010) and also in aging mouse (Benito et al, 2015). This is consistent the dysregulation of H4K12ac being implicated to mediate cognitive impairment in aged mice (Peleg et al, 2010).…”

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

“…Among these, APP/PS1 double transgenic mice are an extensively used model, showing progressive age-related development of Aβ accumulation and cognitive deficits (Jankowsky et al 2001;Trinchese et al 2004;van Groen et al 2006;Meyer-Luehmann et al 2009;Filali et al 2011;Janus et al 2015). Furthermore, previous studies have revealed positive results, such as demonstrating various antioxidants (Garcia-Alloza et al 2010;Varamini et al 2014;Yanagisawa et al 2015), neuroprotective agents (Kilgore et al 2010;Peng et al 2012;Li et al 2014), anti-neuroinflammation (Cherry et al 2015;Guo et al 2015), immune therapy (Sudduth et al 2013;Carrera et al 2013;Zhang et al 2015), and nonpharmacological interventions (Liu et al 2011;Jankowsky et al 2005), which can attenuate or even reserve AD-like pathology in APP/PS1 mice. Unfortunately, none of these potentially useful results have been able to be reproduced in clinical therapies for AD patients.…”