Histone Deacetylases (HDACs) and Alzheimer
In a recent post, I concentrated on the role of HDACs in cancer: Histone Deacetylases (HDACs) and Cancer and mentioned that some HDACs are overexpressed and show very high activities in a number of tumours. Today, I ‘ll focus on the role of HDACs in Alzheimer’s disease, which accounts for 60 to 70% of dementia cases. Taking into account the demographic development – it has been projected that by 2050, people aged 60 and over will account for 22% of the world’s population – and the fact that it affects approx. 6% of people older than 65 years, the WHO stated that “Alzheimer disease (AD) has become a major public health concern…” (Background Paper 6.11; 2013).
There is no way to cure AD so far, the pharmaceutical strategies rather aim at temporarily improving symptoms. Inhibiting HDACs has been recently linked with stimulating the growth of brain cells and memory restoration in animal Alzheimer models (1, overview in 2). Several HDAC inhibitors such as trichostatin A, phenylbutyrate, valproate (Depakote) or SAHA (Vorinostat) induced enhanced memory function in AD mouse models; nevertheless, none of the inhibitors resulted in altered amyloid deposition.
Memory restoration seems to be dependent on the growth of new synapses, which could be induced by the inhibition of multiple HDACs (1). As HDACs have quite different functions in general and in the brain as well, a non-selective inhibition of all HDACs should be avoided (3). Indeed it has been found that less specific inhibition of Class I HDACs was correlated to a better growth of synapses (1).
To facilitate your HDAC related Alzheimer research and screening activities, a number of active enzymes, assay kits and HDAC modulators can be obtained from well-known and highly reliable sources.
4 classes of HDAC enzymes
Four classes of HDACs can be differentiated, all of which are available in active form (produced by BPS Bioscience):
- Class I: HDAC1, HDAC2, HDAC3, and HDAC8
- Class II: HDAC4, HDAC5, HDAC7, HDAC9 (Class IIA) and HDAC6, HDAC10 (Class IIB)
- Class III: SIRT1, SIRT2,SIRT3, SIRT4, SIRT5, SIRT6, SIRT7
- Class IV: HDAC11
Inhibitor Screening Assays
For inhibitor screening campaigns, convenient assays are needed. A comprehensive range of assays against all relevant HDAC enzymes have been recently developed – a complete overview is available here: HDAC inhibitor screening assays. Typical results obtained with the HDAC inhibitor TSA on HDAC1 are shown in Fig. 1. Fig. 2 shows the general principle of the HDAC inhibitor screening assays. Fluorescent-dye molecules are attached to a peptide containing acetyllysine.
Attachment to the peptide quenches the fluorescence of the dye. After treatment of the peptide with deacetylase, the reaction is mixed with a development solution that is specific for non-acetylated lysines. If the acetyl group has been removed from the lysine by the deacetylase, this solution will release the dye allowing for fluorescence. Fluorescence is therefore directly related to HDAC activity.
To characterize and differentiate different members of the HDAC family and to have reference inhibitors for drug screening, well defined modulators are needed. These compounds can either inhibit specific HDACs or show more general effects. Focus Biomolecules offers a range of high quality compounds, such as MS-275, Apicidin, Trichostatin A, BML-210, SAHA (Vorinostat), M-344, Tubastatin A•HCl, HPA (Hexyl-4-pentynoic acid), Na Valproate, Panobinostat, Phenylbutyrate Na, and Romidepsin.
If you are interested to learn more about our comprehensive offer of enzymes, activity assays and modulators, get in touch with me by leaving your questions or comments below.
(1) G. Rumbaugh et al., Pharmacological Selectivity Within Class I Histone Deacetylases Predicts Effects on Synaptic Function and Memory Rescue, Neuropsychopharmacology 40 (10): 2307-16 (2015).
(2) S. Bahari-Javan et al., Histone-acetylation: a link between Alzheimer’s disease and post-traumatic stress disorder?, Front. Neurosci. (2014)
(3) K. Xu et al., Targeting HDACs: A promising therapy for Alzheimer’s disease, Oxidative Medicine and Celllular Longevity 2011: 143269 (2011)