Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease

Sung, You Me; Lee, Taehee; Yoon, Hyuk; DiBattista, Amanda M.; Song, Jung Min; Sohn, Yoojin; Moffat, Emily; Turner, R. Scott; Jung, Mira; Kim, Jung-Su; Hoe, Hyang Sook

doi:10.1016/j.expneurol.2012.10.005

Cited by 122 publications

(93 citation statements)

References 28 publications

(40 reference statements)

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“…7 Furthermore, in a mouse model of AD, the application of HDAC inhibitors attenuates Ab oligomerinduced drebrin loss from dendritic spines, 22 decreases Ab levels, and improves learning and memory. 23 This evidence strongly suggests a critical role of HDAC2 in various aspects of AD pathogeneses, such as the amyloid precursor protein (APP) process, synaptic dysfunction, and memory impairment. The accumulation of HDAC2 also occurs at the beginning at Braak stages I/II, which are characterized by the accumulation of hyperphosphorylated tau protein in the brain, and correlates with cognitive decline.…”

Section: Discussionmentioning

confidence: 99%

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

Liú

Tang

et al. 2017

Molecular Therapy

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Histone deacetylase 2 (HDAC2) plays a major role in the epigenetic regulation of gene expression. Previous studies have shown that HDAC2 expression is strongly increased in Alzheimer's disease (AD), a major neurodegenerative disorder and the most common form of dementia. Moreover, previous studies have linked HDAC2 to Ab overproduction in AD; however, its involvement in tau pathology and other memoryrelated functions remains unclear. Here, we show that increased HDAC2 levels strongly correlate with phosphorylated tau in a mouse model of AD. HDAC2 overexpression induced AD-like tau hyperphosphorylation and aggregation, which were accompanied by a loss of dendritic complexity and spine density. The ectopic expression of HDAC2 resulted in the deacetylation of the hepatocyte nuclear factor 4a (HNF-4A) transcription factor, which disrupted its binding to the miR-101b promoter. The suppression of miR-101b caused an upregulation of its target, AMP-activated protein kinase (AMPK). The introduction of miR-101b mimics or small interfering RNAs (siRNAs) against AMPK blocked HDAC2-induced tauopathy and dendritic impairments in vitro. Correspondingly, miR-101b mimics or AMPK siRNAs rescued tau pathology, dendritic abnormalities, and memory deficits in AD mice. Taken together, the current findings implicate the HDAC2/miR-101/AMPK pathway as a critical mediator of AD pathogenesis. These studies also highlight the importance of epigenetics in AD and provide novel therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

Liú

Tang

et al. 2017

Molecular Therapy

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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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“…Interest in HDAC6 as a possible therapeutic target in the CNS (d'Ydewalle et al, 2012) has grown considerably following discovery of the key role of this enzyme in aggresome formation (Kawaguchi et al, 2003), pathological evidence for its inclusion in Lewy bodies in Parkinson's disease as well as in glial cytoplasmic inclusions in frontotemporal lobar degeneration with TDP-43 inclusions (Ding et al, 2008), and evidence suggestive of a role in Alzheimer's disease (Govindarajan et al, 2012;Sung et al, 2013;Xiong et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Antidepressant-Like Properties of Novel HDAC6-Selective Inhibitors with Improved Brain Bioavailability

Jochems

Boulden

Lee

et al. 2013

Neuropsychopharmacol

149

150

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HDAC inhibitors have been reported to produce antidepressant and pro-cognitive effects in animal models, however, poor brain bioavailability or lack of isoform selectivity of current probes has limited our understanding of their mode of action. We report the characterization of novel pyrimidine hydroxyl amide small molecule inhibitors of HDAC6, brain bioavailable upon systemic administration. We show that two compounds in this family, ACY-738 and ACY-775, inhibit HDAC6 with low nanomolar potency and a selectivity of 60-to 1500-fold over class I HDACs. In contrast to tubastatin A, a reference HDAC6 inhibitor with similar potency and peripheral activity, but more limited brain bioavailability, ACY-738 and ACY-775 induce dramatic increases in a-tubulin acetylation in brain and stimulate mouse exploratory behaviors in novel, but not familiar environments. Interestingly, despite a lack of detectable effect on histone acetylation, we show that ACY-738 and ACY-775 share the antidepressant-like properties of other HDAC inhibitors, such as SAHA and MS-275, in the tail suspension test and social defeat paradigm. These effects of ACY-738 and ACY-775 are directly attributable to the inhibition of HDAC6 expressed centrally, as they are fully abrogated in mice with a neural-specific loss of function of HDAC6. Furthermore, administered in combination, a behaviorally inactive dose of ACY-738 markedly potentiates the anti-immobility activity of a subactive dose of the selective serotonin reuptake inhibitor citalopram. Our results validate new isoform-selective probes for in vivo pharmacological studies of HDAC6 in the CNS and reinforce the viability of this HDAC isoform as a potential target for antidepressant development.

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Mercaptoacetamide-based class II HDAC inhibitor lowers Aβ levels and improves learning and memory in a mouse model of Alzheimer's disease

Cited by 122 publications

References 28 publications

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

Targeting the HDAC2/HNF-4A/miR-101b/AMPK Pathway Rescues Tauopathy and Dendritic Abnormalities in Alzheimer’s Disease

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

Antidepressant-Like Properties of Novel HDAC6-Selective Inhibitors with Improved Brain Bioavailability

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