In his letter Peedicayil  suggests that epigenetic mechanisms, in particular histone deacetylases (HDACs) and gene methylation, might represent a promising target for drug discovery in Alzheimer's disease (AD). In our recent review  we focused on disease modifying drugs in advanced clinical development (Phase II/III). Therefore we did not discuss drugs that specifically exert epigenetic effects, because none of them so far has reached advanced clinical development for AD. However, as suggested by Peedicayil, epigenetic mechanisms in neurodegenerative diseases have been the object of intensive research in recent years and deserve attention because they might soon constitute a novel paradigm in AD arena.
Histone acetylation is dynamically regulated by histone acetyltransferases (HATs) and HDACs. HATs neutralize the positive charge on lysine residues allowing chromatin to adopt a more relaxed structure and to recruit the transcriptional machinery. HDACs reverse lysine acetylation, restore histone positive charge and locally stabilize chromatin architecture . Thus, the level of histone acetylation dramatically affects chromatin condensation and gene transcription. DNA methylation is also involved in histone modification. Methylation of CpG islands in promoter regions is associated with gene silencing and is highly interactive with histone acetylation and the other histone-modifying mechanisms .
Studies of late-onset AD in twins support the notion that risk factors may affect AD pathophysiology through epigenetic mechanisms . On the other hand, some AD risk factors, such as chronic stress , induce strong epigenetic modifications in animal models . Alteration of physiological stress responses, such as those affecting the hypothalamic-pituitary-adrenal axis, may further increase the epigenetic impact of chronic adverse stress in AD . Chronic psychological distress has been also associated with late-life non-AD dementia , but the role of epigenetic mechanisms in this condition has not been investigated so far.
HDAC2, but not HDAC1, is known as a negative regulator of memory . Cognitive function in AD may be affected by an epigenetic blockade of gene transcription. A recent study suggests that this blockade is mediated by HDAC2 in patients with AD and shows that it is potentially reversible in mouse models of neurodegeneration . Non-specific pan-HDAC inhibitors include valproic acid, trichostatin A, sodium 4-phenylbutyrate and vorinostat. All these drugs, however, have been shown to affect, by different mechanisms, Aβ plaque deposition and/or tau hyperphosphorylation . It remains unclear, therefore, whether or not these drugs, endowed with neuroprotective action in vitro, re-instate memory and reverse learning deficits in AD mouse models through Aβ clearance, rather than primarily through HDAC inhibition. The causal involvement of epigenetic mechanisms in AD, if confirmed, may help in understanding failure of clinical trials with disease modifying drugs despite their proven efficacy in Aβ clearing. According to this view, if the epigenetic blockade starts before the clinical onset of AD, then reducing Aβ generation and deposition alone may not be sufficient to rescue cognitive functions. Finally, as with any novel drug treatment, epigenetic modifiers must be carefully considered in terms of safety and tolerability, particularly considering the fundamental role of epigenetics in the regulation of global gene expression patterns. HDAC inhibitors have been initially studied and used in neoplastic diseases, such as haematological malignancies . Vorinostat and romidepsin were first approved for the treatment of cutaneous T cell lymphoma, but the potential therapeutic utility of HDAC inhibitors for non-oncology indications requires more stringent safety profiles. Key safety issues include the long term effects on stem cells and germ cells. Potential effects on human reproduction are not relevant in AD patients (generally beyond the reproductive age), but other effects involving immune function [12, 13] might prevent the use of HDAC inhibitors in AD patients. Furthermore it should be considered that HDAC inhibitors developed for cancer may poorly permeate the blood–brain barrier . Recently a CNS-penetrant HDAC (Class I) inhibitor, EVP-0334, has been developed and studied in a phase I clinical trial for the treatment of AD , but further detailed information has not yet been disclosed.
Identification of subtype- or target-selective HDAC inhibitors, such as for HDAC2 will hopefully provide, in the near future, transcriptional and synaptic effects in neurons, with fewer off target effects, making possible the clinical development of these drugs for AD.