Advances in Genetics and Epigenetic Alterations in Alzheimer’s Disease: A Notion for Therapeutic Treatment

Abstract

Alzheimer’s disease (AD) is a disabling neurodegenerative disorder that leads to long-term functional and cognitive impairment and greatly reduces life expectancy. Early genetic studies focused on tracking variations in genome-wide DNA sequences discovered several polymorphisms and novel susceptibility genes associated with AD. However, despite the numerous risk factors already identified, there is still no fully satisfactory explanation for the mechanisms underlying the onset of the disease. Also, as with other complex human diseases, the causes of low heritability are unclear. Epigenetic mechanisms, in which changes in gene expression do not depend on changes in genotype, have attracted considerable attention in recent years and are key to understanding the processes that influence age-related changes and various neurological diseases. With the recent use of massive sequencing techniques, methods for studying epigenome variations in AD have also evolved tremendously, allowing the discovery of differentially expressed disease traits under different conditions and experimental settings. This is important for understanding disease development and for unlocking new potential AD therapies. In this work, we outline the genomic and epigenomic components involved in the initiation and development of AD and identify potentially effective therapeutic targets for disease control.

An Epigenetic Role of Mitochondria in Cancer

“…H3K27me3 induces gene silencing and regulates cell differentiation, and its dysregulation frequently happens in tumorigenesis [ 393 , 394 ]. Histone methylation reader protein ZMYND11 interacts with histone H3.3K36me3, thus leading to the suppression of tumor growth [ 395 ]. The epigenetic mark H4K16ac of H4 is prone to higher acetylation with age in healthy cells, while it tends to disappear in regions of the genome near age- and AD-dependent genes [ 396 ].…”

Altered Balance of Reelin Proteolytic Fragments in the Cerebrospinal Fluid of Alzheimer’s Disease Patients

“…The ever-growing prevalence of Alzheimer’s disease (AD) is associated with the sporadic presentation of the disease [ 1 , 2 ]. Sporadic AD is a multifactorial disease with environmental contributing causes (mainly age); however, genetic risk factors are also important [ 3 , 4 , 5 ]. Amongst the numerous genes implicated in AD pathogenesis, the most prominent genetic risk factor is the apolipoprotein E (apoE) encoding gene, APOE .…”

Neuroprotective Epigenetic Changes Induced by Maternal Treatment with an Inhibitor of Soluble Epoxide Hydrolase Prevents Early Alzheimer′s Disease Neurodegeneration

“…In the end, offspring of both genotypes of TPPU-treated dams reached similar levels. DNA methylation is a major regulator of gene transcription [ 41 ] and an aberrant DNA methylation pattern is known in AD brain [ 42 ]. It is known that an improved regulation of this epigenetic mechanism during development benefits synaptic plasticity and cognitive function in the offspring [ 41 ].…”

“…Histone deacetylation is a crucial epigenetic mechanism that regulates gene expression and can modulate neurodevelopment and brain function [ 45 ]. Particularly, dysregulation of the transcriptional repressors HDAC1 and 2 are important drivers of neurodegeneration and AD [ 42 , 46 ]. HDAC1 and 2 are negative regulators of synaptic plasticity and memory formation and circumventing its epigenetic blockade would be beneficial against neurodegeneration [ 47 , 48 ].…”

“…Furthermore, epigenetic changes in WT offspring suggest improved neurodevelopment as an acquired resilience against neurodegeneration. The implications of epigenetic changes in the initiation and development of AD are not well understood, but they may fill the gap between genetic and environmental risk [ 42 ].…”