Alzheimer’s disease (AD) is a neurodegenerative disorder(1-3) causing progressive loss of cognitive functions leading to dementia and death.(4) Older age is the highest risk factor for AD (3, 5) and the prevalence of AD rises from 3% among those 65-74years to almost 50% among those >85year(2). An estimated 5.2 million Americans of all ages had AD in 2013(1). It currently affects more than 33.9million people worldwide(4) and is predicted to be affecting more than 80million people worldwide by 2040(3) which makes treating AD a pertinent issue to be dealt with at present.
Epigenetic (defined as reversible regulation of various genome functions, occurring without change in DNA sequence)(6, 7) , modification has recently emerged as one of the pathogenic mechanism for AD(6-8). The three pillars of epigenetic mechanism include DNA methylation, histone modification and non-coding RNA(9). This research mainly focuses on the histone modification in the pathogenesis of cognitive impairment in AD and the therapeutic role of histone deacetylase inhibitor (HDACi) for the same(10-12) . In histones(10, 12, 13) the modification occurs at the N terminal of the molecule which includes histone acetylation(14). Histone acetylation is regulated by the counteracting activities of histone acetyltransferase (HATs), which adds an acetyl group to a lysine residue, resulting in chromatin activation(13, 15) and histone deacetylases(HDAC), which remove acetyl group and linked to chromatin inactivation(14, 16). This relaxes the chromatin structure and allows transcription factors to interact with their target DNA.(10)
Histone acetylation is an important mechanism for memory formation.(17, 18) Recent studies suggest that specific HATs and HDACs are required for memory formation and learning ability in severe neurodegeneration(13). Postmortem studies of AD patients have shown increased HDAC within the hippocampus(19) and lower acetylation over temporal lobe (20). HAT and HDAC influences the level of histone acetylation(14). There are 18 HDCAs that belong to 4 classes according to their sequence homology(11). Among them the HDACs linked to cognitive impairment in AD pathology are thought to be Class 1, HDAC 2 associated with associative and spatial memory impairment.(8) Either activating HAT or inhibiting HDAC can defend histone deacetylation but latter has proven more achievable than former(15)
HDAC inhibitors are classified into 4 main chemical families. 1. Carboxylic acids- eg Sodium butyrate, valporic acid, 4phenylbutyrate acts on Class 1 HDAC. 2. Hydroxamic acid- eg: Trichosatin, SAHA acts on Class 1 and 2 HDCA. 3. Benzamide group- eg: MS275 acts on Class 1 HDAC and 4. Cyclic tetrapeptides- Tapoxin.(15) Researches have focused mainly on class 1 and class 2 HDACi as treatment option for cognitive enhancement in AD.(21-23) The studies conducted on mouse models with AD related neurodegeneration treated by sodium butyrate(24) (Class 1 HDACi) showed rescue of cognitive...