Loss of HDAC5 Impairs Memory Function: Implications for Alzheimer's Disease

Agís‐Balboa, Roberto Carlos; Pavelka, Zsuzsa; Kerimoğlu, Cemil; Fischer, André

doi:10.3233/jad-2012-121009

Cited by 95 publications

(70 citation statements)

References 35 publications

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“…Consistent with this result, the treatment of amygdala slices with TSA causes an enhancement of LTP [188]. Cued fear conditioning was also impaired after HDAC5 knockdown (in 10-month-old mice) or HDAC2 overexpression (in 4-monthold mice) [183,186], confirming a link between histone acetylation and amygdala proper functioning.…”

Section: Histone Acetylation In Synaptic Plasticity and Memorysupporting

confidence: 72%

“…The overexpression of HDAC1 in the adult mouse hippocampus increased this specific form of learning [185]. Furthermore, the loss of HDAC4 (in 2-month-old mice) and HDAC5 (in 10-but not 2-month-old mice) impaired memory functions, with an alteration in the CxFC and the MWM tasks in both cases [186,187].…”

Section: Histone Acetylation In Synaptic Plasticity and Memorymentioning

confidence: 94%

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Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

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Section: Histone Acetylation In Synaptic Plasticity and Memorysupporting

confidence: 72%

Section: Histone Acetylation In Synaptic Plasticity and Memorymentioning

confidence: 94%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

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“…In contrast, restoration of histone acetylation leads to recovery of cognitive performance ( 45 ). More recent studies suggest that there is an urgent need to develop additional selective histone deacetylase (HDAC) inhibitors ( 46 ).…”

Section: Histone Acetylation and Deacetylationmentioning

confidence: 99%

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Hashim

VanItallie

2014

Journal of Lipid Research

120

108

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This article is available online at http://www.jlr.org family, its importance for purposes of this review is minimal.). KBs have been dubbed "metabolism's ugly duckling" because, in the mid-19th century, they were fi rst discovered in large quantities in the urine of patients succumbing to diabetic ketoacidosis. Thus, it is not surprising that physicians of the era considered KBs to be toxic byproducts of impaired carbohydrate metabolism. It took almost half a century for medical scientists to understand that KBs are normal metabolites manufactured by the liver in increasing amounts when dietary sources of carbohydrate and glucogenic amino acids are in short supply ( 1 ). Unfortunately, some physicians still fail to distinguish between the safe "physiological" hyperketonemia that occurs in healthy individuals during fasting or adherence to a ketogenic diet (KD), and the pathological, out-of-control hyperketonemia associated with insulin-defi cient diabetes.When Owen et al. ( 2 ) reported that during a prolonged fast KBs can provide 60% or more of the brain's daily energy requirement (thereby sparing ‫ف‬ 80 g/day of glucose that otherwise would have been derived largely from breakdown of the body's limited protein stores), it was finally acknowledged that, as in Hans Christian Andersen's 1843 fairy tale, the creature fi rst thought to be an ugly duckling was turning out to be an emerging swan. It became evident that the ketogenic response to starvation is an indispensable metabolic adaptation designed by nature to preserve strength and prolong life during times when food is unavailable ( 3 ) .It is now known that (in nondiabetic individuals), owing to the blood's effi cient buffering capacity, plasma KB Abstract Ketone bodies (KBs ), acetoacetate and ␤ -hydroxybutyrate ( ␤ HB), were considered harmful metabolic by-products when discovered in the mid-19th century in the urine of patients with diabetic ketoacidosis. It took physicians many years to realize that KBs are normal metabolites synthesized by the liver and exported into the systemic circulation to serve as an energy source for most extrahepatic tissues. Studies have shown that the brain (which normally uses glucose for energy) can readily utilize KBs as an alternative fuel. Even when there is diminished glucose utilization in cognition-critical brain areas, as may occur early in Alzheimer's disease (AD), there is preliminary evidence that these same areas remain capable of metabolizing KBs. Because the ketogenic diet (KD) is diffi cult to prepare and follow, and effectiveness of KB treatment in certain patients may be enhanced by raising plasma KB levels to у 2 mM, KB esters, such as 1,3-butanediol monoester of ␤ HB and glyceryl-tris-3-hydroxybutyrate, have been devised. When administered orally in controlled dosages, these esters can produce plasma KB levels comparable to those achieved by the most rigorous KD, thus providing a safe, convenient, and versatile new approach to the study and potential treatment of a variety of diseases, including epilepsy, ...

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“…39 Our data open the possibility that alterations of metal metabolism and redox regulatory mechanisms operating in HDAC5-depleted cardiac cells might be a critical link between pressure overload and cardiac hypertrophy. 40 As reported by Agis-Balboa et al, loss of HDAC5 might be involved in Alzheimer disease, 41 a pathology that is often associated with disregulation of metal homeostasis and oxidative stress. [42][43][44][45][46] Similarly, metal regulation has been proposed as being a critical link between oxidative stress and ageing leading us to hypothesize that deregulation of HDAC5 might be a key mechanism in the free-radical and mitochondrial theories of ageing.…”

Section: Discussionmentioning

confidence: 84%

Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition

et al. 2017

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The US FDA approval of broad-spectrum histone deacetylase (HDAC) inhibitors has firmly laid the cancer community to explore HDAC inhibition as a therapeutic approach for cancer treatment. Hitting one HDAC member could yield clinical benefit but this required a complete understanding of the functions of the different HDAC members. Here we explored the consequences of specific HDAC5 inhibition in cancer cells. We demonstrated that HDAC5 inhibition induces an iron-dependent reactive oxygen species (ROS) production, ultimately leading to apoptotic cell death as well as mechanisms of mitochondria quality control (mitophagy and mitobiogenesis). Interestingly, adaptation of HDAC5-depleted cells to oxidative stress passes through reprogramming of metabolic pathways towards glucose and glutamine. Therefore, interference with both glucose and glutamine supply in HDAC5-inhibited cancer cells significantly increases apoptotic cell death and reduces tumour growth in vivo; providing insight into a valuable clinical strategy combining the selective inhibition of HDAC5 with various inhibitors of metabolism as a new therapy to kill cancer cells.

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Loss of HDAC5 Impairs Memory Function: Implications for Alzheimer's Disease

Cited by 95 publications

References 35 publications

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

Ketone body therapy: from the ketogenic diet to the oral administration of ketone ester

Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition

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