Decreased HDAC 1 Gene Expression in Patients with Alzheimer ’ s Disease

One of the commonest neurodegenerative diseases, Alzheimer’s disease (AD), is characterized by progressive decline in memory and cognitive functions with inexorable neurodegeneration in brain. Histone-tail acetylation have been known to be associated with some crucial neurologic functions, thus, the enzymes regulating this events such as HDAC1 are associated with such neurodegenerative diseases like AD. The research objective was to document the levels of HDAC1 expression in peripheral lymphocytes harvested from patients clinically diagnosed with AD. Fifty patients diagnosed with AD, and 49 ageand sex-matched controls were recruited to the study. Total RNA was extracted, cDNA was synthesized, and HDAC1 expressions were tested using quantitative real-time polymerase chain reaction (qRT-PCR). HDAC1 expression was found significantly attenuated in patients with AD compared with the controls (p<0.001). The research data suggested that lower expression levels of HDAC1 may have an impact in the etiology or disease course of AD. Address for correspondence: Dr. Ali Bayram Firat University Elazig High School of Health Sciences, Elazig, Turkey E-mail: ak.ali@hotmail.com INTRODUCTION Histone acetylation is an important regulatory mechanism of chromatin remodeling by taking role in various biological mechanisms through fundamental alterations in gene expression (Roth et al. 2001). In those acetylationdeacetylation events, histone deactylases (HDACs), together with histone acetyl transferases (HATs), act as a rheostat to maintain homeostasis in protein acetylation and transcription events with pivotal roles especially in neurons (Langley et al. 2005; Kazantsev and Thompson 2008). HDACs often function as gene expression suppressors via dictating heterochromatin formation, which is a tightly packed, condense version of chromatin with certain LysineArginine residues remained deactylated on core histone proteins silencing gene expression (Gallinari et al. 2007). Our current knowledge of the effect of histone acetylation on neuronal activities was mostly achieved by the studies on HDACs and their inhibitors (HDACi). Histone tail acetylations have been known to be associated with some crucial neurological functions including memory formation, neuronal plasticity and learning (Alarcón et al. 2004; Korzus et al. 2004; Vecsey et al. 2007). Human HDAC proteins are divided into four main classes, of which class-I and II HDACs are mostly studied and implicated with central nervous system and related neurodegenerative disorders (Alarcón et al. 2004). HDAC1 belongs to the class I HDACs, and it is majorly implicated with memory function of fear extinction. HDAC inhibitors improve the memory formation in murine models of Alzheimer’s disease (AD) suggesting that histone acetylation is associated with memory (Alarcón et al. 2004; Fischer et al. 2007; Govindarajan et al. 2011). It was suggested by proteome based HDACi studies that HDAC1 and HDAC2 can be more potent HDACS in memory formation. Those two closely work together, and have nearly identical structures carrying crucial developmental roles in neuronal differentiation (Montgomery et al. 2009; Salisbury and Cravatt 2007). DNA damage and neuronal death are among the underlining etiopathogenesis factors of many neurodegenerative disorders including AD, and studies indicated that they can be prevented by increased HDAC1 activity (Kim et al. 2008). AD is characterized by progressive decline in memory and cognitive functions with inexorable neurodegeneration in brain eventually causing dementia. The majority of dementia cases 178 ALI BAYRAM, FERIDUN AKKAFA, AHMET OZER AND REMZI YIGITER are diagnosed with AD (Qiu et al. 2009). It is one of the leading causes of mortality and morbidity in elderly. It was estimated that there were over 35 million individuals with dementia worldwide in 2010 and social impact and economic burden of this alignment is increasing (Wortmann 2012). AD and dementia represent a significant health care problem for Turkish society as well. A crosssectional, population based study reported that AD prevalence in a Turkish metropolis reached 11% in population over 70 years old, which is comparable to that of the statistics with the Western European counterparts (Gurvit et al. 2008). Underlying neuropathological alterations include extracellular amyloid plaques and intracellular tangles causing progressive dysfunction and death of nerve cells in brain. The actual causative factor of the disease is unknown, but many possible risk factors are spelled including inflammation, oxidative stress, genetics and epigenetics (Mattson 2004). In the etiology, variable combinations of genetics and environmental factors are plausible especially for the lateonset AD covering over 90% of the patients (Zawia et al. 2009). Against growing body of studies aiming to understand the nature of the disease and develop therapeutic measures, AD is still a crucial social and health issue of our aging community. Epigenetic changes are accounted for one of the important way of molecular regulatory mechanisms, and may contribute to the AD pathogenesis [as reviewed in (Fisher A 2014)]. Thus, epigenetics studies promise a new scope in AD and dementia research for the development of better diagnostic and therapeutic solutions. In the present study, the researchers aimed to determine HDAC1 expression levels at mRNA level in patients with AD and compare the results with those in healthy volunteers.