Shewale et al., Biol Syst 2013, 2:3 DOI: 10.4172/2329-6577.1000114 Open Access Review Article Volume 2 • Issue 3 • 1000114 Biol Syst ISSN: BSO, an open access journal The Potential Role of Epigenetics in Alzheimer’s Disease Etiology Shantanu J Shewale 1 , Ryan M Huebinger 2 , Michael S Allen 1,3 and Robert C Barber 4 * 1 Department of Forensic and Investigative Genetics, University of North Texas Health Science Center Fort Worth, USA 2 Department of Surgery, University of Texas Southwestern Medical Center at Dallas, USA 3 Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, USA 4 Department of Pharmacology & Neuroscience, University of North Texas Health Science Center Fort Worth, USA Abstract Alzheimer’s disease (AD) is an etiologically heterogeneous disorder. While many genes have been found to be associated with Early and Late onset AD, a large portion of the predicted heritability remains unidentifed. Here we review AD pathology, with an overview of AD genetics. In addition, we review epigenetic mechanisms and the current literature that suggests a relationship between epigenetic mechanisms and AD pathology. The genome wide association studies conducted to date can explain a percentage of AD cases. The remainder may be best explained by complex interactions between epigenetic and environmental factors that differ between individuals. *Corresponding author: Robert C. Barber, Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, USA. Tel: (817) 735-2056, Fax: (817) 735-2091; E-mail: robert.barber@unthsc.edu Received July 26, 2013; Accepted August 16, 2013; Published August 19, 2013 Citation: Shewale SJ, Huebinger RM, Allen MS, Barber RC (2013) The Potential Role of Epigenetics in Alzheimer’s Disease Etiology. Biol Syst 2: 114. doi:10.4172/2329-6577.1000114 Copyright: © 2013 Shewale SJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. hypothesis postulates that the disease is the result of an imbalance between the production and degradation of β-Amyloid [9]. Normally, β-Amyloidis degraded by peptidases such as neprilysin, insulin- degrading enzyme, and endothelin-converting enzyme [2]. Tis central theory has strong support, from work beginning with Alois Alzheimer [1]and continuing through the deduction of the sequence of the amyloid beta protein [10] and cloning of mutations in APP [11,12], PSEN1 and PSEN2genes [13,14]. A recent development that signifcantly strengthened the amyloid hypothesis was the discovery by Jonssonet al. [15] of an APP mutation that reduces production of β-Amyloid and is protective against Alzheimer’s disease as well as age-related cognitive decline.It has been hypothesized that β-Amyloid protein deposition precedes neurofbrillary tangles [16], cell loss, and vascular damage [17]. In transgenic murinemodels, β-Amyloid deposition developed prior to tangles [18]. Working witha transgenic mouse model, Xu et al. [16] described an accumulation of β-Amyloid precipitateda loss of solubility of intracellular cytosolic proteins such as glycolytic enzymes and members of the chaperone family. β-Amyloidplaques have also been thought to induce neuronal oxidative stress, resulting in phospholipid peroxidation and protein oxidation in AD brain [19]. Te second hallmark of AD is the presence of hyper- phosphorylated microtubule associated protein tau (MAPT). Te tau protein is primarily expressed in neurons [20] and has been shown to be involved with tubulin polymerization as well as acting to stabilize microtubules against depolymerization [21], stabilize microtubules responsible for axonal transport [20], increase neuritic stability, impact the rate of neurite elongation, and increase net microtubule stability [2,22]. Diferent iso forms of the tau protein are expressed due to alternative RNA splicing, and all iso forms are capable of forming the fbrillary tangles that are a hallmark of AD [23] , [23,24]. A balance between kinases (ex. GSK-3Beta, CDK5) and phosphatases (ex. PP-1,PP2) plays a role in regulating tau phosphorylation [2]. Tau Keywords: Alzheimer’s; Kinases; Epigenetics; Etiology Introduction Alzheimer’s disease(AD) was characterized by Aloysius “Alois” Alzheimer in 1907, and was based upon his observations and treatment of a 51 year old patient named August ‘D’[1]. Te patient showed symptoms of short term memory loss, unusual behavior and the neuropathological characteristics that have become the hallmarks of Alzheimer’s disease [1]. AD is the most common type of dementia, which is a term that describes a wide range of symptoms such as trouble with memory, language, ability to focus, reasoning skills, and visual perception [2]. Alzheimer’s disease is a progressive disease that is fatal given that no other cause of death intervenes. It’s also the most common form of age-related neurodegenerative dementia, a serious health problem in the industrialized world, and is currently the 6 th leading cause of death in the United States [3]. Te current fgures from the Alzheimer’s Association states that one in three seniors will die with AD or another form of dementia. One in eight people 65 years of age and older have AD [3]. When examining people that are 85 and older, the incidence of AD increases to one in two individuals [3]. It is estimated that currently within United States, over 5 million people have AD, and this is expected to rise to over 13 million by the year 2050 3 .Currently, it is estimated that the care provided by family, and other unpaid caregivers of people with dementia is valued at about $210 billion [4]. Pathogenesis Te two hallmarks of AD are extracellular Beta (β)-Amyloid plaques and neurofbrillary tangles [5,6]. β-Amyloid plaques are formed from cleavage of Amyloid Precursor Protein (APP), which is an integral membrane protein that is expressed throughout the body and particularly concentrated in neuronal synapses. Te primary function of APP is not fully understood, but it has been implicated in neurite extension and synaptic plasticity [4]. β and Gamma (γ) secretases cleave APP to produce fragments that aggregate together to form the β-Amyloid plaques. β-secretase is an integral membrane as partyl protease encoded by the β-site APP-cleaving enzyme1 (BACE1) gene [7]. Te other secretase that is involved in the production of β-Amyloid, γ-secretase, is composed of 4 subunits: presenilin 1(PSEN1), presenilin 2(PSEN2), nicrastin, and APH1 [2,4], where the active site consists of presenilin [2]. A widely held theory of AD pathogenesis is the amyloid cascade hypothesis, which states that the deposition of the β-Amyloidpeptide in the brain is the initiating event in disease pathology [8]. Te amyloid B i o l o g i c a l S y s t e m s : O p e n A c c e s s ISSN: 2329-6577 Biological Systems: Open Access