Epigenetics: A novel therapeutic approach for the treatment of Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is the most common type of dementia in the elderly. It is characterized by the deposition of two forms of aggregates within the brain, the amyloid β plaques and tau neurofibrillary tangles. Currently, no disease-modifying agent is approved for the treatment of AD. Approved pharmacotherapies target the peripheral symptoms but they do not prevent or slow down the progression of the disease. Although several disease-modifying immunotherapeutic agents are in clinical development, many have failed due to lack of efficacy or serious adverse events. Epigenetic changes including DNA methylation and histone modifications are involved in learning and memory and have been recently highlighted for holding promise as potential targets for AD therapeutics. Dynamic and latent epigenetic alterations are incorporated in AD pathological pathways and present valuable reversible targets for AD and other neurological disorders. The approval of epigenetic drugs for cancer treatment has opened the door for the development of epigenetic drugs for other disorders including neurodegenerative diseases. In particular, methyl donors and histone deacetylase inhibitors are being investigated for possible therapeutic effects to rescue memory and cognitive decline found in such disorders. This review explores the area of epigenetics for potential AD interventions and presents the most recent findings in this field.

Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: biochemical, epigenetic and functional correlates

“…Abbreviations: a-tub, a-tubulin; IR, immunoreactivity; OLE, oleuropein aglycone; QC, glutaminyl cyclase; wt, wild type. * p < 0.05, ** p < 0.01, *** p < 0.001. novel promising therapeutic strategy to treat AD (Adwan and Zawia, 2013). Therefore, the search of a causative link of the beneficial effects of OLE on AD-like pathology of 12-month-old TgCRND8 mice brought us to investigate whether OLE affected the level of histone acetylation in the brains of our wt and Tg mice.…”

“…We also checked the level of histone acetylation in the oldest treated and untreated animals to ascertain whether the protective effects of OLE supplementation also involved epigenetic modifications. In fact, recent data indicate that epigenetic changes are implicated in learning and memory (Graff et al, 2012) and these modifications have been suggested as potential targets for AD therapeutics (Adwan and Zawia, 2013). Accordingly, we investigated the functional effects of OLE in aged animals by assessing in brain slices whether its administration in vitro was able to counteract dysfunctions of transgene-induced long-term potentiation (LTP) in the CA1 hippocampal area.…”

Curcumin Inhibits the AKT/NF-κB Signaling via CpG Demethylation of the Promoter and Restoration of NEP in the N2a Cell Line

“…In general, DNA methylation is associated with blockade of gene expression (14). Several lines of evidence now demonstrate that aberrant DNA methylations of genes in AD are implicated in the initiation and progression of AD (32). Neprilysin (NEP), a zincdependent metallopeptidase, serves as the major physiological Aβ-degrading enzyme (9).…”

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

“…Recent literature shows that epigenetic regulations could stand as a valuable therapeutic strategy for AD [148]. Particularly, several studies report acetylation dysregulations associated with pathological markers of this disease.…”