Tubastatin A/ACY-1215 Improves Cognition in Alzheimer's Disease Transgenic Mice1

Zhang, Ling; Liu, Cui; Wu, Jie; Tao, Jingjing; Sui, Xiaolong; Yao, Zhigang; Xu, Yanfeng; Huang, Lan; Zhu, Hua; Shen, Sheng; Qin, Chuan

doi:10.3233/jad-140066

Cited by 151 publications

(125 citation statements)

References 52 publications

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“…In agreement with our findings, HDAC6 inhibition was recently reported to induce autophagic flux in primary cardiomyocytes [52] and to facilitate the autophagic degradation of A and hyperphosphorylated tau [53].…”

Section: Accepted Manuscriptsupporting

confidence: 91%

HDAC6 inhibition induces mitochondrial fusion, autophagic flux and reduces diffuse mutant huntingtin in striatal neurons

Guedes-Dias

Proença

Soares

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Striatal neurons are vulnerable to Huntington's disease (HD). Decreased levels of acetylated alpha-tubulin and impaired mitochondrial dynamics, such as reduced motility and excessive fission, are associated with HD; however, it remains unclear whether and how these factors might contribute to the preferential degeneration of striatal neurons. Inhibition of the alpha-tubulin deacetylase HDAC6 has been proposed as a therapeutic strategy for HD, but remains controversial - studies in neurons show improved intracellular transport, whereas studies in cell-lines suggest it may impair autophagosome-lysosome fusion, and reduce clearance of mutant huntingtin (mHtt) and damaged mitochondria (mitophagy). Using primary cultures of rat striatal and cortical neurons, we show that mitochondria are intrinsically less motile and more balanced towards fission in striatal than in cortical neurons. Pharmacological inhibition of the HDAC6 deacetylase activity with tubastatin A (TBA) increased acetylated alpha-tubulin levels, and induced mitochondrial motility and fusion in striatal neurons to levels observed in cortical neurons. Importantly, TBA did not block neuronal autophagosome-lysosome fusion, and did not change mitochondrial DNA levels, suggesting no impairment in autophagy or mitochondrial clearance. Instead, TBA increased autophagic flux and reduced diffuse mHtt in striatal neurons, possibly by promoting transport of initiation factors to sites of autophagosomal biogenesis. This study identifies the pharmacological inhibition of HDAC6 deacetylase activity as a potential strategy to reduce the vulnerability of striatal neurons to HD.

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Section: Accepted Manuscriptsupporting

confidence: 91%

HDAC6 inhibition induces mitochondrial fusion, autophagic flux and reduces diffuse mutant huntingtin in striatal neurons

Guedes-Dias

Proença

Soares

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…In fact, the induction of genes implicated in synaptic plasticity, the formation of new dendritic spines, and the increase in pCamKII observed in mice treated with CM-414 may at least partially underlie the restoration of memory in these transgenic mice. Finally, the inhibition of HDAC6 may facilitate the degradation of misfolded proteins, such as Aβ and pTau (Sung et al, 2012;Yu et al, 2013;Zhang et al, 2014). Although different studies have demonstrated that HDACi or PDE5i improved cognitive deficits in animal models of AD, their role on amyloid pathology is controversial (Benito et al, 2015;Cuadrado-Tejedor et al, 2011b;Garcia-Barroso et al, 2013;Puzzo et al, 2009;Qing et al, 2008;Ricobaraza et al, 2009;Rumbaugh et al, 2015;Zhang and Schluesener, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, these enzymes have been described as negative regulators of memory consolidation (Guan et al, 2009;McQuown et al, 2011). In contrast, HDAC6 regulates microtubule function and stability via tubulin acetylation (Guan et al, 2009;Hubbert et al, 2002), and dampening HDAC6 activity promotes tau and Aβ clearance (Cook et al, 2012;Sung et al, 2012;Zhang et al, 2014). Notably, HDAC2 and HDAC6 are overexpressed in the cortex and hippocampus of AD patients, although the cause and effect of this upregulation remains unknown (Ding et al, 2008;Graff et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

Cuadrado‐Tejedor

García‐Barroso

Sánchez‐Arias

et al. 2016

Neuropsychopharmacol

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The targeting of two independent but synergistic enzymatic activities, histone deacetylases (HDACs, class I and HDAC6) and phosphodiesterase 5 (PDE5), has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMPresponsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission. Thus, CM-414 may serve as the starting point to discover balanced dual inhibitors with an optimal efficacy and safety profile for clinical testing on AD patients.

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“…However, this can also be due to other HDAC6 functions, such as its ubiquitin-binding ability [38,180,181]. Importantly, inhibition of HDAC6 with selective Tubulin acetylation: responsible enzymes, biological functions and human diseases inhibitors promotes tubulin acetylation and significantly improves learning-based performance in mice with bamyloid-induced hippocampal lesions [182,183].…”

Section: Tubulin Acetylation Human Diseases and Therapeutic Implicatmentioning

confidence: 99%

Tubulin acetylation: responsible enzymes, biological functions and human diseases

Yang

2015

Cell. Mol. Life Sci.

222

184

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Microtubules have important functions ranging from maintenance of cell morphology to subcellular transport, cellular signaling, cell migration, and formation of cell polarity. At the organismal level, microtubules are crucial for various biological processes, such as viral entry, inflammation, immunity, learning and memory in mammals. Microtubules are subject to various covalent modifications. One such modification is tubulin acetylation, which is associated with stable microtubules and conserved from protists to humans. In the past three decades, this reversible modification has been studied extensively. In mammals, its level is mainly governed by opposing actions of α-tubulin acetyltransferase 1 (ATAT1) and histone deacetylase 6 (HDAC6). Knockout studies of the mouse enzymes have yielded new insights into biological functions of tubulin acetylation. Abnormal levels of this modification are linked to neurological disorders, cancer, heart diseases and other pathological conditions, thereby yielding important therapeutic implications. This review summarizes related studies and concludes that tubulin acetylation is important for regulating microtubule architecture and maintaining microtubule integrity. Together with detyrosination, glutamylation and other modifications, tubulin acetylation may form a unique 'language' to regulate microtubule structure and function.

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Tubastatin A/ACY-1215 Improves Cognition in Alzheimer's Disease Transgenic Mice1

Cited by 151 publications

References 52 publications

HDAC6 inhibition induces mitochondrial fusion, autophagic flux and reduces diffuse mutant huntingtin in striatal neurons

HDAC6 inhibition induces mitochondrial fusion, autophagic flux and reduces diffuse mutant huntingtin in striatal neurons

A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer’s Disease Mice

Tubulin acetylation: responsible enzymes, biological functions and human diseases

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