tubacin and Alzheimer-Disease

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, which is characterized by the primary risk factor, age. Several attempts have been made to treat AD, while most of them end in failure. However, with the deepening study of pathogenesis of AD, the expression of HDAC6 in the hippocampus, which plays a major role of the memory formation, is becoming worth of notice. Neurofibrillary tangles (NFTs), a remarkable lesion in AD, has been characterized in association with the abnormal accumulation of hyperphosphorylated Tau, which is mainly caused by the high expression of HDAC6. On the other hand, the hypoacetylated tubulin induced by HDAC6 is also fatal for the neuronal transport, which is the key impact of the formation of axons and dendrites. Overall, the significantly increased expression of HDAC6 in brain regions is deleterious to neuron survival in AD patients. Based on the above research, the inhibition of HDAC6 seems to be a potential therapeutic method for the treatment of AD. Up to now, various types of HDAC6 inhibitors have been discovered. This review mainly analyzes the HDAC6 inhibitors reported amid 2010-2020 in terms of their structure, selectivity and pharmacological impact towards AD. And we aim at facilitating the design and development of better HDAC6 inhibitors in the future.

Topics: Acetamides; Alzheimer Disease; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Models, Molecular; Molecular Structure; Neuroprotective Agents

We have identified chemical probes that act as dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors (>1 log unit difference versus class I HDACs) to decipher the contribution of HDAC isoforms to the positive impact of dual-acting PDE5 and HDAC inhibitors on mouse models of Alzheimer's disease (AD) and fine-tune this systems therapeutics approach. Structure- and knowledge-based approaches led to the design of first-in-class molecules with the desired target compound profile: dual PDE5 and HDAC6-selective inhibitors. Compound 44b, which fulfilled the biochemical, functional and ADME-Tox profiling requirements and exhibited adequate pharmacokinetic properties, was selected as pharmacological tool compound and tested in a mouse model of AD (Tg2576) in vivo.

Topics: Alzheimer Disease; Cell Line; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; Drug Design; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Molecular Structure; Neuroglia; Phosphodiesterase 5 Inhibitors; Structure-Activity Relationship

Histone deacetylase 6 (HDAC6), a unique cytoplasmic deacetylase, likely plays a role in neurodegeneration by coordinating cell responses to abnormal protein aggregation. Here, we provide in vitro and in vivo evidence that HDAC6 interacts with tau, a microtubule-associated protein that forms neurofibrillary tangles in Alzheimer's disease. This interaction is mediated by the microtubule-binding domain on tau and the Ser/Glu tetradecapeptide domain on HDAC6. Treatment with tubacin, a selective inhibitor of tubulin deacetylation activity of HDAC6, did not disrupt HDAC6-tau interaction. Nonetheless tubacin treatment attenuated site-specific tau phosphorylation, as did shRNA-mediated knockdown of HDAC6. Proteasome inhibition potentiated HDAC6-tau interactions and facilitated the concentration and co-localization of HDAC6 and tau in a perinuclear aggresome-like compartment, independent of HDAC6 tubulin deacetylase activity. Furthermore, we observed that in Alzheimer's disease brains the protein level of HDAC6 was significantly increased. These findings establish HDAC6 as a tau-interacting protein and as a potential modulator of tau phosphorylation and accumulation.

Topics: Aged; Alzheimer Disease; Anilides; Brain; Cell Compartmentation; Cell Line; Down-Regulation; Enzyme Inhibitors; Female; Histone Deacetylase 6; Histone Deacetylases; Humans; Hydroxamic Acids; Male; Microtubules; Middle Aged; Neurofibrillary Tangles; Neurons; Organelles; Phosphorylation; Protein Binding; Protein Structure, Tertiary; RNA, Small Interfering; tau Proteins